Substituted imidazoles or their pharmaceutically acceptable salts and pharmaceutical composition

 

(57) Abstract:

Substituted imidazole formula I

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in which R6- alkyl, C2-C6; R7- vinyl, low cycloalkenyl; phenylalkyl in which Alchemilla part contains 2-6 carbon atoms; 2 - or 3-furyl; biphenylyl; phenoxyphenyl; phenylthio; pyridylthio or 3-mercaptophenyl, methylthio; R8means -(CH2)n-CH2OH or-C(O)H; R13- dehydrator or-COOH; n = 1-10 and r = 1-2; or their pharmaceutically acceptable salts. The connection I and these salts possess antihypertensive activity. Described pharmaceutical composition comprising compound I or its specified salt. 2 S. and 2 C.p. f-crystals, 8 PL.

The present invention relates to new substituted imidazoles which can be used in pharmaceutical compositions and used both independently and in combination with other drugs, especially diuretics and nonsteroidal anti-inflammatory drugs (spit), as well as pharmaceutical compositions based on them.

Connections matching the present invention inhibit the action of the hormone angiotensin II (AII) and therefore useful for the treatment of hypertension caused by assigning angiotesin I, which then turns into AII under the action of the enzyme, specific for angiotensin. Hormone AII strongest stimulator of increasing pressure in the vessels, which is the main cause of high blood pressure in both animals of different species, including rats and dogs and in humans. Connections matching the present invention inhibit the activity of AII on the respective receptors of target cells and thereby prevent a rise in blood pressure caused by the interaction of a specified hormone with its receptor. The result of an assignment of the compounds according to the present invention mentioned animals (mammals), suffering from hypertension caused by AII, blood pressure in the body of these animals are able to reduce. Connections matching the present invention, moreover, useful in the treatment of heart failure, caused by blockage of blood vessels. The purpose of the connection that meets the present invention, in combination with a diuretic, such as furosemide or hydrochlorothiazide, as a separate phase of treatment (when the first stage is prescribed diuretic) or in the form of a physical mixture of these drugs increases antiguamente with nonsteroidal anti-inflammatory drug (spit) can prevent renal failure, often caused by destination spit.

Tiled European patent application N 0253310, published January 20, 1988, discloses that certain way substituted imidazoles block AII receptors and, therefore, applicable to mitigate the occurrence of hypertension caused by angiotensin, and also for the treatment of heart failure, caused by blockage of blood vessels. These imidazoles have the formula

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The imidazoles of the present invention differ from similar compounds described in the aforementioned application EPA 0253310, groups, R7and R8in positions 4 and 5 of the imidazole ring. In the proposal EPA 0253310 radicals R7and R8defined as follows:

R7means H, F, Cl, Br, I, NO2, CF3or CN;

R8denotes H, CN, alkyl with 1-10 carbon atoms, alkenyl with 3-10 carbon atoms or fluoro-substituted derivatives; phenylalkyl, aliphatic portion of which contains from 2 to 6 carbon atoms;

-(CH2)mimidazol-1-yl; -(CH2)m- 1,2,3-triazolyl, possibly substituted by one or two groups selected from such groups as CO2CH3or alkyl with 1-4 carbon atoms; -(CH2)mtetrazolyl.

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gruppenreisen.

Pals al. (Pals et al. Circulation Research, 1971, v.29, p.673) describe the connection to the endogenous hormone AII, constricting blood vessels, the remainder of sarcolysin (in position 1) and alanine (position 8) to produce oktapeptid that blocks the action of AII on blood pressure in rats subjected to spinal tap. It was found that this (Sar1Ala8) similar AII, which is initially defined as P-113, and then called saralasin (Saralasin), is the most effective means of combating the harmful effects of AII, although in itself the specified analog like most so-called peptide antagonists of AII also cause unwanted side effects. It was shown that saralasin lowers blood pressure in mammals and humans in those cases where the (high) blood pressure depends on the circulation of AII in the blood [see above work Pals et al. as well as a monograph: Streten and Anderson. Manual of hypertension, so 5: Clinical pharmacology of drugs against hypertension" Ed. by Doyle; Scientific publishing house Elsevier, 1984, page 246 (Streeten and Anderson. Handbook of Hypertension, v.5: "Clinical Pharmacology of Antihypertensive Drugs", ed. A. S. Doyle; Elsevier Science Publishers, B. V., 1984, p.236)] However, due to its active nature, saralasin, generally speaking, in those cases is to as saralasin is a peptide, its pharmacological action is relatively short and is shown only after the appointment by injection (parenterally), whereas the effect of the drug entered tematicheskie (orally), that is, through the oral cavity, and inefficient. Due to the fact that therapeutic application of peptide blockers hormone AII significantly limited due to their inefficiency in the introduction tematicheskie, and also because of short time steps, they are suitable as a pharmaceutical standard in research.

Some famous ones antihypertensive agents inhibit the enzyme, called enzyme converting angiotensin (EPA), responsible for the conversion of angiotensin I to AII. Therefore, such agents can be called inhibitors EPA or inhibitors of the enzyme transformations (INRM). Available commercially such INRM, as captopril and enalapril.

Clinical trials show that in 40% of cases the body affected by hypertension, immune to treatment type EPI. But it is only in conjunction with the IEP to appoint receiving diuretic, such as furosemide or hydrochlorothiazide how effective normalization of blood pressure in most cases is awesomee from renin, in the normal state, regulated by renin. Although the imidazoles, proposed in the present invention, operate on a different mechanism, but rather 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. The Merch company Co-markets the drug under the brand name "Vaseretic" (Vaseretic), representing the combination of enalapril maleate (product type EPI) and hydrochlorothiazide, which is a diuretic. About the use of diuretics in conjunction with the EPI for the treatment of hypertension when first prescribed diuretic, and at the next stage, INRM, or simply assign the mixture of these drugs has been reported in publications Keaton and Campbell (T. Keeton K. Campbell W. B. Pharmacol. Rev. 1981, v.31, p.81), and Weinberg (Weinberg M. H. Medical Clinics of N. America, 1987, v.71, p.979). It also describes the use of diuretics in combination with saralasin to enhance protivogipertonicheskoe effect.

Dann (see Dunn M. J. Hospital Practice, 1984, v.19, R. 99) wrote that nonsteroidal anti-inflammatory drugs (spit) cause renal failure in patients with renal pompertuzat and high levels of AII in the blood plasma. The purpose Otago reception at different stages of treatment, either in the form of a physical mixture) capable of preventing referred to renal failure. It was shown that saralasin suppresses renal effect compression of blood vessels in dogs, caused by indomethacin and meclofenamate, see Sato and researcher. (Satoh et al. Circ. Res. 1975, v.36/37, suppl.I, pp.1-89) and Blasingame al. (Blessingham et al. Am. Journ. Physiol. 1980, v.239, p.F360). It was shown that captopril (product type ice) counteracts caused by indometacinum and with renal character compression of blood vessels in dogs, accompanied megapotamicum hemorrhage; see the work of Wang and al. (Wong et al. J. Pharmacol. Exp. Ther. 1980, v.219, p.104).

According to the present invention proposed new substituted imidazoles having the properties of antagonists against the hormone angiotensin II and applicable as tools against hypertension in animals, as well as the pharmaceutical composition on the basis of them.

Substituted imidazoles, proposed according to the present invention, unite General formula I

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where R1means a radical of the formula

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R2means H;

R3means H;

R6means alkyl with 2-6 carbon atoms;

R7means vinyl, lower cycloalkenyl; phenylalkyl, to the 3-or mercaptophenyl; methylthio;

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R11means hydrogen;

R13means or-COOH;

R16means hydrogen;

R17means hydrogen;

R31means hydrogen;

X represents carbon-carbon single bond;

n has a value from 1 to 10;

r has a value from 1 to 2;

subject: R1is not in the ortho-position; R13located in the ortho - or meta-position, or pharmaceutically acceptable salts, having antihypertensive activity.

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

Pharmaceutically acceptable salts include metal salts (inorganic salts) and organic salts. The list of salts given in ringtonescom the formulary (Remington's Pharmaceutical Scinces, 1985, 17th ed. p.1418). Any specialist in this field is well known that suitable type of salt selected with regard to its physical and chemical stability, flowability, hygroscopicity and solubility. For the reasons mentioned above, preferred are salts of potassium, sodium, calcium and ammonium.

Obijeski carrier and a compound of formula I in an effective amount. Farbkomposition can be used for the treatment of animals suffering from hypertension and heart failure caused by blockage of blood vessels. The pharmaceutical compositions can optionally contain one or more drugs, such as diuretics or non-steroidal anti-inflammatory drug (spit). The way to prevent kidney failure in animals, caused by appointment spit, including the compounds of formula I at any stage of treatment or in the form of a physical mixture with spit. Connections matching the present invention can also be used as diagnostic agents in the study system the renin-angiotensin.

The synthesis.

The new compounds of 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 the necessary chemical reactions. Specialists in the field of organic synthesis well known that the functional group of the imidazole and other parts of the molecule compounds must comply with the proposed chemical transformations. As p is fair group, conditions unprotect, methods of activation position on 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. The protective group must be compatible with the reaction conditions. The restriction imposed on the replacement of the group in respect of their compatibility with the reaction conditions, it is obvious for any person skilled in the art and may require the use of one of the alternative methods described in this section.

Scheme 1 shows the possible ways of obtaining the proposed compounds I.

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As can be seen from scheme 1, compounds of formula 3 can be obtained by direct alkylation of imidazole 1 protected adequately by benzylamino, tosylate or mesilate 2 in the presence of a base: see the path). It is preferable to obtain a metal salt of imidazole reaction of imidazole with 1 acceptor of protons, such as MH, where M is lithium, sodium or potassium, in a solvent such as dimethylformamide (DMF), or by conducting the reaction of the imidazole of formula 1 with a metal alkoxide of the formula MOR, DG is DG aprotic solvent, such as dimethylformamide. Salt of imidazole were dissolved in an inert aprotic solvent such as DMF, and treated with a suitable alkylating agent 2. In another case, the imidazole 1 could alkilirovanii benzylamino formula 2, where X is bromine or chlorine, 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 from 20°C to the boiling temperature of the solvent for 1 to 10 hours, for Example 4-nitroaniline intermediate compound of the formula For R1is a 4-NO2and R2and R3hydrogen can be obtained by direct alkylation of imidazole 1 4-nitrobenzylamine, tosylate or mesilate in the presence of a base.

Since R7and R8different, you get a mixture of two products (3b and 3c) alkylation, which regioisomers in which R7and R8are interchangeable. If R8represents CHO, alkylation proceeds in such a way that the benzyl group is attached primarily to the nearest nitrogen atom. These isomers have different physical and biological properties. They can struck crystallization.

From all the studied experiments found that the first washed isomer of this pair, possessing higher biological activity compared to the isomer, washed out later.

According to another variant of any derivative 4 benzylamine with appropriate functional groups can be converted into Imin 6 treatment allumination 5 in an inert solvent, such as benzene, toluene, etc. in the presence of catalytic amount of para-toluenesulfonic acid or molecular sieves [see the Work of Engel and Steglich (Engel N. W. Steglich - Liebigs Inn. Chem. 1978, p.1916)] or in the presence of alumina [see the work of texie-bule (Texier-Boulet F. Synthesis, 1985, p.679)] the Resulting Imin 6 can be cilitate in N-benzylimidazole formula 3 pentachloride phosphorus PCl5, phosphorus oxychloride POCl3or triphenylphosphine PPh3in dichloroethane in the presence of a base such as triethylamine (see the above work of Engel and Steglich).

Allumination 5 it is easy to obtain from amino acids by the reaction Dakine West (see Dakin, H. D. West, R. J. Biol. Chem. 1928, v.78, p.95, 745) or according to one or another modification [see Steglich and Hofle (Steglich W. Hofle g Angew. Chem. Int. Ed. Engl. 1969, v.8, p.981; Hofle, G. Steglich W. H. Vorbruggen Angew. Chem. Int. Ed. Ed. Engl. 1978, v.17, p.569; Steglich W. Hofle, G. Ber. 1969, v.102, t. Lett. 1984, p.2977)] or a halo-, a-tosyl or methylketone by appropriate substitution reactions, well known specialist in this field.

Benzylamine 4 functional groups can be synthesized from the corresponding benzylamine, tosilata or nelfinavir 2 by substitution of the nitrogen nucleophile according to methods well known to the person skilled in the art. This substitution can be accomplished with the use of azide ion, ammonia or anion phthalimide, etc., in a neutral solvent such as dimethylformamide, dimethylsulfoxide, etc., or in conditions of phase transfer. Bentelhalal can be synthesized by one of numerous methods benzylguanine, well known to the person skilled in the art, for example by bromirovanii derivatives of toluene with N-bromosuccinimide in an inert solvent such as carbon tetrachloride, in the presence of the initiator radical formation, such as benzoylperoxide, with the temperature increase prior to the removal of the solvent.

A variety of derivatives of toluene can be synthesized by electrophilic substitution. These include nitration, sulfonation, phosphorylation, alkylation by Friedel is to Olah G. A. "Reaction Friedel-crafts and related reactions" (Friedel-Grafts and Related Reactions, v.1-5, New York Intersciense, 1965)]

Another way of synthesis of functionally substituted benzylamino is through chlorotoluene the corresponding intermediate compounds, then in turn aromatic. Therefore, appropriately substituted benzene ring can be klimatisierung, for example, formaldehyde and hydrochloric acid HCl in the presence or in the absence of an inert solvent, such as chloroform, carbon tetrachloride, light petroleum ether or acetic acid. As a catalyst or condensing agent, you can add one of Lewis acids such as zinc chloride ZnCl2or mineral acid, for example phosphoric [see Fuson, R. C. McKeever c.H. Org. Reactions, 1942, I, p.63]

According to other variant N-benzylimidazole 3 can also be prepared as shown in scheme 1b), through the formation of R6-substituted amidine 7 and appropriately substituted benzylamine 4, which in turn reacts with a-haloketones, hydroxyketone 8, a-halolligiga or hydroxyaldehyde (see Kunckell F. Ber. 1901, v.34, p.637).

As shown in scheme 1a), imidazole 1 is ctionality, such as ortho-, meta - and para-cyanobenzaldehyde, mesylates or tozilaty. As shown in scheme 1c), the NITRILES of formula 9 can hydrolyze to carbolic acid of formula 10 by the action of the strong acid or alkali. Preferred treatment of a mixture of concentrated aqueous hydrochloric acid with glacial acetic acid (volume ratio 1:1) at temperatures of distillation solvent for 2-96 hours or handling 1H. a solution of sodium hydroxide in an alcohol solution, such as ethanol or ethylene glycol, for 2-96 hours at temperatures of 20oC to the temperature of distillation of the solvent. If there is another nitrile group, it will also be hydrolysed. The nitrile group can be hydrolyzed in two stages, when the first stage is realized by mixing sulfuric acid with the formation of the amide, and the following conduct hydrolysis with sodium hydroxide or mineral acid with the formation of carboxylic acid 10.

NITRILES 9 can be converted to the corresponding derivative 11 tetrazole different methods using hydrating acid. Thus, the nitrile can be heated with sodium azide and ammonium chloride in dimethylformamide at temperatures of from 3 doctitle, when tetrazol obtained by 1,3-dipolar cycloaddition triamcinolone or azides triamcinolone to appropriately substituted the nitrile, as described in scheme 6.

Source imidazole compounds 1 easy to synthesize by any of numerous standard techniques. For example, you can cilitate allumination 5 with ammonia or equivalent substances (see D. Davidson et al. J. Org. Chem. 1937, v.2, p.319) in the corresponding imidazole, as shown in figure 1. The corresponding oxazol can also be tailored to the imidazole 1, as a rule, the influence of ammonia or amines (see J. W. Cornforth Cornforth, R. H. J. Chem. Soc. 1947, 96).

Figure 2 presents a number of alternative methods of obtaining imidazole 1. Numbering and General formula, see scheme 1. Equation (a) shown in scheme 2 shows that carrying out the reaction of a suitable R6-substituted complex ether 12 imidate with appropriately substituted a-hydroxy or a-haloketones or aldehyde 8 in ammonia gives the imidazole of formula 1 (see Dziuron P. Schumack W. Archiv. Pharmaz. 1974, p.307, 470).

Source imidazole compounds 1, where R7and R8both represent hydrogen, can be obtained according to equation (b) conducting the meeting Grimett M. R. Adv. Heterocyclic Chem. 1970, v.12, p.103).

As shown by equation 2c), imidazole 15 (where R7hydrogen, and R8the group CH2OH) can be obtained by treatment of ester 12 imidate 1,3-dihydroxyacetone 14 in ammonia by well-known methods (see Archive der Pharmacie, 1974, p.307, 470). Halogenoalkane imidazole 15 or any of imidazole, in which R7and R8represent hydrogen, is best done by conducting the reaction with one or two equivalents of N-haloacrylates in a polar solvent such as dioxane or 2-methoxyethanol at a temperature lying in the range 40-100oC for 1-10 hours the Reaction of halogenated imidazole 16 benzylamino 2, carried out as shown in scheme 1, gives the corresponding benzylimidazole 17, where R7halogen, and R8radical, CH2OH. This operation is described in U.S. patent 4355040. Alternatively, the imidazole 17 can be obtained by the method described in U.S. patent 4207324.

The compounds of formula 17, in addition, can be obtained by processing the original imidazole compounds 1, where R7and R8both represent hydrogen, a suitable benzylamino with subsequent functionalization of R7and R8using formaldehyde as e is shows the imidazoles 1 can also be obtained by conducting the reaction R6-substituted amidino 18 with a-hydroxy or a-haloketones or aldehyde 8, as described Kunckel F. Ber. 1901, v.34, p.637.

The compounds of formula 1, where R8radical, CH2OH, can also be obtained, as shown by the equation (e). Namely, imidazoles 1 were obtained, as described Reiter L. A. J. Org. Chem. 1987, v.52, p.2714). Hydroxymethylpropane connection I give hydroxymethylimidazole Ia, as described Kempe al. in U.S. patent 4278801.

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As shown in scheme 3, path a) for benzylimidazole 17, in which R8means radical, CH2OH, hydroxymethylene group can be easily converted to the corresponding halide, mesilate or toilet by one of the methods, many of which are well known to the person skilled in the art. It is preferable to convert the alcohol 17 in chloride 25 thionyl chloride in an inert solvent at a temperature of 20oC to the temperature of distillation of the solvent.

Chloride 25 may be replaced by various nucleophiles by one of the methods of carrying out the reaction of nucleophilic substitution, a well-known specialist in this field. So, for education cyanomethylphosphonate 26 can take izbitogo derived acetic acid 27 to one of the known methods. These techniques include those that were previously described for the hydrolysis of NITRILES of formula 9. Examples of desirable acids and bases for the hydrolysis include mineral acids such as sulfuric, hydrochloric, and mixtures of each with 30-50% acetic acid (in those cases when the problem occurs solubility), and hydroxides of alkali metals such as sodium hydroxide or potassium. The hydrolysis reaction is conducted by heating to temperatures of 50-160oC for 2-48 hours Carboxylic acid 27 can be atrificial one of the known methods, without affecting the remaining parts of the molecule. It is preferable to conduct the reaction within 2-48 hours at the boiling solution containing hydrochloric acid and methyl alcohol, to obtain a complex ester 28.

Ester 28 can hydrolyze to carboxylic acid 27, for example, after will be carefully designed group R1, R2and R3. You can use various techniques, both acidic and basic. For example, the connection 28 is stirred with 0.5 N. potassium hydroxide solution in methyl alcohol, and if the base is soluble, it is stirred 1H. the sodium hydroxide solution at a temperature of 20oC to temperature distillation eat this or that method. As shown by path b), the acylation can be carried out with the use of 1-3 equivalents of allvalid or anhydride in a solvent such as simple diethyl ether, tetrahydrofuran, methylene chloride, etc. in the presence of a base such as pyridine or triethylamine. Alternatively, the connection 17 can be allievate by conducting the reaction with a carboxylic acid and dicyclohexylcarbodiimide (DCC) in the presence of catalytic amounts of 4-(N,N-dimethylamino)pyridine (DMAP) according to the method, which was described Hassner (Hassner A. Tet. Lett. 1978, v.46, p.4475). The preferred technique is to process connection 17 with a solution of carboxylic acid anhydride in pyridine, preferably in the presence of catalytic amounts of DMAP at temperatures of 20-100oC for 2-48 h

As shown by path c), a simple ether 30 can be obtained from alcohol 17 different methods, such as treatment of compound 17 in a solvent such as dimethylformamide or dimethylsulfoxide, tert.-the piperonyl potassium, sodium hydride, etc., with subsequent treatment of the radical R11L at 25oC for 1-20 h, provided that L represents halogen, tosylate or mesilate.

According to another variant, the processing of compound 17 one-patago connection 25 one to three equivalents of radical MOR, where M is sodium or potassium, at 25oC for 2-10 h or in a solvent of the formula R11OH, or in a polar solvent such as dimethylformamide, etc., also gives the final product a simple ether 30.

A simple ether 30 can also be obtained by heating compound 17 at 60-160oC for 3-15 hours in an environment of connection R11OH, also containing inorganic acid is hydrochloric or sulfuric.

In various procedures of synthesis does not require that the group R1, R2and R3remained the same from the original connection to the final product, but rather that they often change, pursuing well-known reaction at the intermediate stages, as shown in the diagrams below. All the transformations shown in schemes can be also executed on the terminal aromatic ring, such as biphenylenes the ring.

Compounds of structural formula I, where X is a bond of carbon-carbon marked 80, can be synthesized as shown in scheme 4.

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Equation (a) shows that biphenylene connection 80 can be obtained by alkylation of imidazole 1 suitable galoretelevision connection 79 according to the General method described in scheme 1.

Required galoot is isano in "Organic Reactions", 1944, v.2, p.6, in order to obtain the intermediate compounds 83, which in turn halogenous. Halogenoalkane may be accompanied by heating compound 83 in boiling inert solvent such as carbon tetrachloride, for 1-6 h in the presence of N-haloacrylates and initiator of the reaction, such as azobisisobutyronitrile (equation b).

Equation (c) shows that the derivatives of the intermediate 83, in which R13is in position 2' (connection 83a) can be obtained by the method described in J. Org. Chem. 1976, v.41, p.1320, that is, the method of the Diels-alder reaction (Diels-Alder) accession 1,3-butadiene to styrene 84 followed by aromatization of the intermediate 85.

Alternatively substituted biphenylene connection 83, in which R13-COOH, and their esters 89 can be obtained by the method represented by equation (d), which as a key intermediate compounds includes oxazolinone connection (see Meyers A. J. Michelich E. D. J. Am. Chem. Soc. 1975, v.97, p.7383).

Then the equation (e) shows that catalyzed by Nickel cross-linking arizonavov excreted by gelbeseiten gives biphenyldiol, which, in turn, can hydrolyze one of the means

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can be obtained from the nitrile compounds, in which R13means CN, according to the methods described in scheme 1 for the equation (c) and figure 5 for the equation (c).

However, the preferred ways of getting tetrazoles described in scheme 5 for the equations (a) and (b). Connection 90 can be obtained 1,3-dipolar-cyclopentadiene of azides triamcinolone or triphenylamine to appropriately substituted the nitrile 83, as represented by equation (a). "Alkyl" means a normal alkyl with 1-6 carbon atoms, and cyclohexyl.

An example of such technology described Cosima al. (S. Kozima et al. - Organometallic 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 triarylamine remove acidic or basic hydrolysis, and tetrazol you can protect a group of trityl carrying out the reaction with Fritillaria and triethylamine to obtain compound 91. The above bromination with N-bromosuccinimide and Dibenzoyl peroxide network connection 92. Alkylation of compound 1 appropriately substituted benzylamino in the conditions described above, followed by removing the protective group of trityl way is stated you can use other protective groups, such as para-nitrobenzyl and 1-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 (Greene, "Protective Groups in Organic Synthesis", Wiley-Interscience, 1980).

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Various 2-substituted imidazoles can be obtained by conducting the reaction of a protected 2-trimethylsilylimidazole with a suitable electrophile, which can then be removed as desired. The appropriate methodology described Pinkerton and Teams (Pinkerton F. H. Thames, S. F. J. Het. Chem. 1972, v.9, p.67).

Alternatively, the group R can be entered catalyzed by Nickel cross-coupling of Grignard reagents (Grignard) 2-methylthiotetrazole (scheme 6), as described Wenkert and Ferreira; Wenkert al. Sugimura, Taka (Wenkert, E., Ferreira, T. W. J. Soc. Chem. Commun. 1982, p.840; E. Wenkert et al. J. Chem. Soc. Chem. Commun. 1979, p.637; Sugimura H. Takei H. Bull. Chem. Soc. Jap. 1985, v.58, p.664). 2-Methylthiotetrazole can be obtained by the method described in German patent 2618370 and therein references.

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Reaction dipyridamole ether (229) with a Grignard reagent receive ketone (230)

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As shown in figure 8, if the imidazole in position 4 and/or 5 - attached aldehyde (see connection 231), the reaction of this compound with organometal, gives alcohol 232, which can, in turn, translate into specific functional derivative, a well-known specialist in this field.

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Aldehyde 233, in turn, can be synthesized from the corresponding alcohol 17 by various methods, well known to experts in this field, including oxidation reactions using chloramine Pisidia (XXII), ceriatone of cerium nitrate and ammonium, as well as oxidative reaction Swarna (Swern).

Similarly dealkilirovanie hydroxymethylimidazole derived 1, in which R8radical, CH2OH, can be converted to the aldehyde.

Connection 238, in which Ar is a para-biphenylyl, para-phenoxyphenyl or group of heteroaryl, characterized in determining the radical R, can be obtained by linking arylmethylidene derived ArM, where M ZnBr, Me3Zn, B(OH)2etc. with holometabola 237 in the presence of a catalyst of a transition metal, such as palladium, Nickel, platinum, zirconium, etc. (scheme 9a). Alternatively, the imidazole metal derived 239 can be associated with arylhalides and obtain thus the connection 238 (scheme 9b).

Arylmethyl derivatives 240 you can get used>2M', where M' ZnBr, etc. as shown in the diagram 9c.

Connection 241 can be obtained, as shown in figure 9d, by binding of alkenyl or alkynylamino derived AM or the corresponding alkene or alkyne AH connection 237.

Similarly dealkilirovanie the imidazoles 1, in which R7bromine or iodine, can be subjected to coupling reaction, are presented on figures 9a-d, a relatively catalyzed by transition metal coupling reaction, see manual GEK "Palladium reagents in organic synthesis" (Heck R. C. "Palladium Reagents in Organic Synthesis", Ch.6,7,8; New York: Acad. Press), as well as the links to other sources.

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The compounds of formula I, in which R7-Alchemilla or substituted Alchemilla group or substituted Alchemilla group, and double or triple bond carbon-carbon not adjacent to the imidazole ring, when, for example, R7represents (CH2)4CH=CH(CH2)vAr, where v is not zero, can be obtained using various methods of increasing the circuit, and coupling reaction chains (these reactions are well known to the person skilled in the art, including the reaction presented on figures 3 and 9.

UNSD, can be obtained as shown in scheme 10.

2-Alkylimidazole-4,5-dicarboxylic acid 242, obtained by the method, which was developed Farger and Pimen (Fargher R. G. Pymen F. L. J. Chem. Soc. 1919, v. 115, p.217), can be translated into their corresponding complex diesters 243 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.

Further ester 243 can be turned into its metal salt by conducting the reaction with methoxide, ethoxide or sodium hydride or other base in a suitable solvent, such as dimethylformamide, in the presence of an acid acceptor such as potassium carbonate or sodium. The obtained Sol next alkylate appropriately substituted benzylphosphonic 2 to obtain benzylimidazole 244. The above sequence of reactions alkylation can also be accomplished by subjecting the heating or distillation of solvent bentelhalal (toilet or mesilate) 2 with imidazole 243 in the environment of a solvent, such as dimethylformamide, in the presence of the absorber acid, such as potassium carbonate or sodium.

Complex fluids 244 can be restored lithium hydride and aluminia of dialcohol 245 manganese dioxide in an inert solvent, such as tetrahydrofuran, gives as a product mainly aldehyde 247 with a small amount of dialdehyde 246. Crystallization or chromatographic separation of compounds 246 and 247 followed by the Wittig reaction of compound 247 with appropriately substituted arrangements.therefore in an inert solvent, such as tetrahydrofuran, gives the quality of the product 4-arylalkyl-5-hydroxymethylimidazole 248. Further oxidation connection 248 periodata proposed dess-Martin (Dess-Martin), see J.Org. Chem. 1983, v.48, p.4155, as well as manganese dioxide, pyridinium chlorochromate, 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 R3if you want to get a 4-arylalkyl-imidazol-5-carboxaldehyde 249.

Oxidation of compound 249, for example, a combination of manganese dioxide with cyanide ion, see Kouri al. (Corey, E. J. et al. J. Am. Chem. Soc. 1968, v.90, p.5616), and Sam and al. (Sam D. J. et al. J. Am. Chem. Soc. 1972, v. 94, p.4024), gives the quality of the product 4-arylalkylamines-5-carboxylic to brisout cycle with 3-8 carbon atoms and their stereoisomers, Z and E around the double bond in compounds 248, 249, 250.

The imidazoles represented by the formula 251, where X is chlorine, bromine or iodine, and E - electronicmedia group: ester, keto, nitro, alkylsulfonyl, etc. can be subjected to reactions of nucleophilic aromatic substitution, see Schubert and Simon (Schubert H. Simon H. Jumar A. Z. Chem. 1968, pp. 62-63), where tsepliaeva group X is substituted by a nucleophile, such as sulfur, carbon or nitrogen, to obtain adducts 252 (scheme 11).

This reaction can be done in an alcohol solvent such as methyl alcohol, or digitoxigenin a solvent such as dimethyl sulfoxide, at a temperature of from room temperature to the temperature of distillation of the solvent. Sometimes nucleophile has to turn in his anion to make this connection more nucleophilic. For example, thiophenol boiled in the presence of sodium methoxide and holometabola. Other nucleophiles include arylthiol, heteroallyl.

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Connections matching the present invention, and methods of obtaining them will become more clear when considering the following examples, which, however, do not limit the invention. In these examples, unless otherwise indicated, all temperatures are in degrees centigrade scale (Celsius), and the share and interest in the CLASS="ptx2">

2-n-propylimidazol-4,5-dicarboxylic acid obtained by the method of Porgera and Pimen (Fargher R. G. Pymen F. L. J. Chem. Soc. 1919, v.115, p. 217), with a melting point of 257oC (dec.), taken in quantity 17,14 g (86,6 mm, 1 EQ), 400 ml of methyl alcohol and 38,1 ml (534 mm, 6 EQ) acetylchloride was stirred under precautions (add acetylchloride to methyl alcohol is characterized by a very strong ekzotermicheskie). The mixture was subjected to boiling solvent for the night. Next, the solvent was removed by vacuum, and then was added 100 ml of water and 10h solution of sodium hydroxide until then, until the pH value reached 7. The aqueous mixture was extracted with three portions of ethyl acetate, then the organic layers were combined, obezvozhivani using magnesium sulfate, the solvent was removed in vacuum to obtain 12 g of the product as white solid.

Recrystallization from a mixture of hexane with ethyl acetate gave 11,41 g of the product as a white solid (yield 58% ) with a melting point 162,0-164,5oC.

Characteristics NMR (CDCl3): 3,95 (s, 6N); 2,78 (t, 2H); 1,83 (t of t, 2H, J=7,7 Hz); of 0.97 (t, 3H, J=7 Hz).

IR spectrum (neat connection): 1735 cm-1.

The analysis forms the

Part B. Obtaining 4-IU Tyl-2-[N-triphenylmethyl(1H-Tetra Zol-5-yl)]biphenyl.

Mixed 4-methylbiphenyl-2-nitrile (receipt described in European patent application 0253310 published 20.01.1988) in an amount of 10 g (51.7 mm, 1 EQ), chloride tri-n-butyanova in the amount of 14 ml (51.7 mm, 1 EQ), sodium azide in the amount of 3.4 g (51.7 mm, 1 EQ) and xylene in a quantity of 50 ml of the Reaction mixture was subjected to distillation of the solvent for 64 h, then cooled to room temperature. Then added 10h NaOH in the amount 6,10 ml (0,061 mm, 1.2 EQ) and Fritillaria in the number 14,99 g (53,8 mm, 1.04 EQ), then these substances were 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 0oC for 1.5 hours Then the resulting solid was filtered, washed twice with portions of water 55 ml and once with a mixture (3:2) heptane with toluene, taken up in 55 ml, then for nights spent dehydration under high vacuum to obtain 19,97 g of the product as a pale yellow powder with a melting point 148-155oC (decomp.). Next of these solids was prepared a mixture of 75 ml of ethyl acetate, which was filtered to obtain 15 g of the product as light yellow); 7,53-to 7.18 (m, 13H); 7,02-6,84 (m, N); of 2.25 (s, 3H).

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Part C. Obtain 4-bromo methyl-2-[N-triphenyl methyl-(1H-Tetra Zol-5-yl)] biphenyl, comparative experience.

Mixed 4-IU Tyl-2-[N-triphenylmethyl-(1H-Tetra Zol-5-yl)] biphenyl in the number 52,07 g (109 mm, 1 EQ), and 19.4 g of N-bromosuccinimide (109 mm, 1 EQ), 1 g of benzoyl peroxide and 300 ml of carbon tetrachloride. The mixture was subjected to boiling for 2.5 hours Then the reactants were cooled to room temperature and was filtered to succinimide. Then the filtrate was concentrated, and the residue was ground into powder with a simple ester and was obtained as a product of the first pickup 36 g of a substance with a melting point of 129.5-133,0oC (decomp.).

Characteristics NMR (CDCl3): 4,37 (CH2Br).

The resulting material is suitable for further transformations.

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Part D. Obtaining 4,5-dicarboxy-2-n-Pro saws-1-[(2'-(N-triphenylmethyl-(1H-Tetra Zol-5-yl))biphenyl-4-yl)methyl]imidazole.

At room temperature to a solution of 10 g of 4,5-dicarbamate C-2-n-propylimidazol (44,2 mm, 1 EQ) in dimethylformamide was added 1.06 g of sodium hydride (44,2 mm, 1 EQ). It was observed foaming and gas development. The temperature was raised to 60oC for 15 min for complete dissolution of hydride NAT is 24,64 g of 4-Bromma Tyl-2-[N-triphenylmethyl(1H-Tetra Zol-5-yl)] biphenyl (44,2 mm, 1 EQ). After 24 h the solvent was removed in vacuo, and the residue was subjected to thin-layer chromatography in a mixture of hexane with ethyl acetate (75:25 ratio), 100% ethyl acetate on silica gel and as a result received 15,78 g (51% yield) of a white glassy substance, suitable for further transformations.

By recrystallization from ethanol there was obtained a sample for analysis in the form of white crystals with a melting point 124,0 output reached 125.5oC.

Characteristics NMR (CDCl3): 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); of 0.85 (t, 3H, J=7 Hz).

IR-spectrum (nerdball.): 1718 cm-1.

Analysis calculated for the formula C43H38N6O4: C 73,49; H THE 5.45; N 11,96.

Found: C 73,23; H 5,48; N 12,22.

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Part E. Obtaining 4,5-dihydroxymethyl-2-n-Pro saws-1-[(2'-[N-triphenylmethyl(1H-Tetra Zol-5-yl)]biphenyl-4-yl)methyl]imidazole.

4,5-Dicarboxy-2-n-Pro saws-1-[(2'-[N-triphenyl methyl-(1H-tetrazol-5-yl)bi phenyl-4-yl)methyl]imidazole in the number of 9.88 g (14,1 mm, 1 EQ) was dissolved in a minimum amount of tetrahydrofuran. This solution is slowly added dropwise introduced a 1M solution of lithium aluminum hydride in tetrahed is then quickly cooled by the method Steinhardt (see guide Fieser Fieser, v.1, p.584) as follows. To the first reaction mixture was carefully added to 0.66 ml of water, then of 0.66 ml of 15% NaOH, and then another of 1.97 ml of water. After stirring for 72 h was all fine precipitate, which was filtered slowly over a zeolite filter brand CeliteTM. The filtrate was obezvozhivani using magnesium sulfate, and the solvent was removed in vacuum. The result has been 8,83 g yellow vitreous recrystallizes substances. This is an intermediate substance was suitable for subsequent transformations.

Characteristics NMR (dimethylsulfoxide-d6): of 7.82 (d, 1H, J=9 Hz); 7.68 per-7,28 (m, N); 7,05 (d, 2H, J=9 Hz); 6.87 in (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=8.7 Hz); of 0.77 (t, 3H, J=7 Hz).

IR-spectrum (nerdball. ): 3300 ush. 3061, 1027, 1006, 909, 732, 699 cm-1.

Analysis calculated for the formula C41H38N6O2H2O: C 74,07; H THE 6.06; N 12,64.

Found: C 74,06; H 5,95; N Up 11,86.

Part F. Obtain 5-hydroxy methyl-2-n-Pro saws-1-[(2'-(N-triphenylmethyl(1H-Tetra Zol-5-yl))biphenyl-4-yl)methyl] imida evil-4-carboxaldehyde and 2-n-Pro saws-1-[(2'-(N-triphenylmethyl(1H-Tetra Zol-5-yl))biphenyl-4-yl)methyl] imide angry-4,5-dicarboxyl the ash in the number 8,56 g (13.2 mm, 1 EQ) was dissolved in a minimum amount of tetrahydrofuran and added to a mixture 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 was filtered through a zeolite filter brand CeliteTM. The filter residue was washed with tetrahydrofuran, and the solvent from the filtrate was removed in vacuum. The residue was subjected to thin-layer chromatography in a mixture of hexane with ethyl acetate at a ratio of 1:1 to 100% ethyl acetate on silica gel to obtain the dialdehyde, washed first, and also of 1.25 g of tannic vitreous 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, 2H, 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=7,7 Hz); of 0.77 (t, 3H, J=7 Hz).

IR-spectrum (nerdball.): 1697, 1672 cm-1.

Analysis for the formula C41H34N6O2: C 76,62; H 5,33; N 13,07.

Found: C 76,46; H 5,54; N 12,94.

Product subsequent leaching was 4-of hydroxyethylamide evil-5-carboxaldehyde representing a light-yellow solid with a melting point 164,5-166,0oC.

Nature, =9 Hz); 6,97-to 6.80 (m, 8H); vs. 5.47 (t, 1H, J=7 Hz); from 5.29 (s, 2H); 4,63 (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 spectrum (Nujol): 1668 cm-1.

Analysis for the formula C41H36N6O2(H2O)a 0.1: C 76,16; H 5,64; N 12,84.

Found: C 76,02; H Are 5.36; N 12,84.

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Part G. Obtain 5-hydroxy methyl-2-n-propyl-1-[(2'-(N-triphenyl methyl-(1H-tetrazol-5-yl))bi phenyl-4-yl)methyl]-4-vinylimidazole.

a 2.5 M Solution of n-utility in tetrahydrofuran, taken in an amount of 1.70 ml (4,3 mm, 2.1 EQ) was added dropwise to a suspension of bromide methyltriphenylphosphonium taken to the number of 1.53 g (4.3 mm, 2.1 EQ) in 50 ml of tetrahydrofuran at 0oC in a gas environment of nitrogen.

The suspension turned into a dark yellow solution, to which was further added 1.31 g of 5-hydroxy methyl-2-n-propyl-1-[(2-(N-triphenyl methyl-(1H-tetrazol-5-yl))bi phenyl-4-yl)methyl] imida evil-4-carboxaldehyde (2 mm, 1 EQ), dissolved in a minimal amount of tetrahydrofuran. The obtained turbid light yellow solution was stirred over night at room temperature. Then the solution was diluted with ethyl acetate and washed with three portions of water. The organic layer was obezvozhivani using magnesium sulfate, the solvent was removed in Vacu is wearing these components is 1:1 to obtain 620 mg (yield 48%) of a white glassy substance.

Characteristics NMR (dimethylsulfoxide-d6): 7,79 (d, 1H, J=7 Hz); a 7.62 (t, 1H, J=7 Hz); at 7.55 (t, 1H, J=7 Hz); was 7.45 (d, 1H, J=7 Hz); 7,41-to 7.18 (m, N); 7,06 (d, 2H, J=9 Hz); 6,95-to 6.80 (m, 8H); 6,80-6,55 (m, 1H); 5,73 (d of d, 1H, J=17.3 Hz); 5.17 to (s, 2H); 5,10 (t, 2H, J=7 Hz); of 5.05 (d of d, 1H, J= 12.3 Hz); 4,28 (d, 2H, J=7 Hz); is 2.37 (t, 2H, J=7 Hz); 1.50 in (t of q, 2H, J= 7,7 Hz); 0,78 (t, 3H, J=7 Hz).

IR-spectrum (nerdball.): 1029, 1006, 909, 733, 698 cm-1.

Analysis for the formula C42H38N6OH2O: C 76,34; H 6,10; N 12,72.

Found: C 76,49; H 5,88; N To 12.52.

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Part H. Obtain 2-n-Pro saws-1-[(2-(N-triphenylmethyl-(1H-Tetra Zol-5-yl))biphenyl-4-yl)IU Tyl]-4-vinylimidazole-5-carboxaldehyde.

Preparing a mixture of 470 mg of 5-hydroxymethyl-2-n-Pro saws-1-[(2-(N-triphenylmethyl(1H-Tetra Zol-5-yl))biphenyl-4-yl)IU Tyl] -4-vinylimidazole (0,73 mm, 1 EQ), 341 mg of periodate Na (Dess-Martin) (0.80 mm, 1.1 EQ), obtained as described in J. Org. Chem. 1983, v.48, p.4155, and 10 ml of methylene chloride, which was stirred overnight in a nitrogen atmosphere. The solvent was removed in vacuo, and the residue was subjected to thin-layer chromatography in a mixture of hexane with ethyl acetate in the ratio of these components is 3:2 over silica gel to obtain the product 310 mg (yield 66%) of a white glassy substance.

Characteristics NMR (dimethylsulfoxide-d6): to 9.91 17.3 Hz); 5,52 (s, 2H), 5,47 (d of d, 1H, J=12.3 Hz); 2.49 USD (t, 2H, J=7 Hz); 1.57 in (t of q, 2H, J=7,7 Hz); of 0.79 (t, 3H, J=7 Hz).

IR-spectrum (nerdball.): 1658 cm-1.

Analysis calculated for the formula C42H36N6O(H2O)0,50: C 77,63; H 5,74; N 12,93.

Found: C 77,53; H 5,73; N 12,64.

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Part I. Getting 2-n-Pro saws-1-[2'-(1H-tetrazol-5-yl))bi phenyl-4-yl)methyl]-4-vinylamide evil-5-carboxaldehyde.

Preparing a mixture of 330 mg of 2-n-Pro saws-1-[(2'-(N-triphenyl methyl-(1H-tetrazol-5-yl))bi phenyl-4-yl)methyl]-4-vinylamide evil-5-carboxaldehyde, 1.65 ml triperoxonane acid, 1.65 ml of water and 1.65 ml of tetrahydrofuran, which was stirred at room temperature. After 8 h, the mixture was neutralized to pH 7 10h. NaOH solution, after which the solvent was removed under vacuum. The residue was subjected to thin-layer chromatography in a mixture of hexane with ethyl acetate in the ratio of these components is 1:1 to 100% ethyl alcohol to obtain 270 mg of the product as a white glassy substance.

Characteristics NMR (dimethylsulfoxide-d6): 9,92 (s, 1H); 7,65 is 7.50 (m, 1H); 7,50 for 7.12 (m, 3H); to 7.09 (d, 2H, J=9 Hz); 6.89 in (d, 2H, J=9 Hz); 6,11 (d of d, 1H, J=17.3 Hz); of 5.55 (s, 2H); of 5.45 (d of d, 1H, J=12.3 Hz); 2.63 in (t, 2H, J=7 Hz); of 1.64 (t of q, 2H, J=7,7 Hz); of 0.90 (t, 3H, J=7 Hz).

IR spectrum (Nujol): 1680 cm-1.

C for 2 h and was stirred solution of 31.5 g of 4(5)-hydroxy methyl-2-n-propylimidazol and 50,06 g N iodosuccinimide in a mixture of 560 ml of 1,4-dioxane and 480 ml of 2-methoxyethanol. Then the solvents were removed under vacuum. The resulting solids were washed with distilled water, and then dried to obtain 54.6 g of product as a yellow solid with a melting point 169-170oC.

Characteristics NMR (dimethylsulfoxide-d6): 12,06 (ush.s, 1H); to 5.08 (t, 1H); 4,27 (d, 2H); 2.50 each (t, 2H); 1,59 (dual.d, 2H); from 0.84 (t, 3H).

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Part B. Obtaining 4-iodine-2-n-propylamide evil-5-carboxaldehyde.

The solution to 35.8 g of 5-hydroxy methyl-4-iodine-2-n-propylimidazol in 325 ml of glacial acetic acid was added dropwise at 20oC for 1 h 290 ml of a 1N aqueous solution of suryamaninagar. The resulting mixture was stirred at 20oC for 1 h Then reacted mixture was diluted with water, brought to pH 5-6 with an aqueous solution of sodium hydroxide and was 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 product was subjected to recrystallization from 1-chlorobutane to get ice NMR (CDCl3): 11,51 (ush.s, 1H); 9,43 (s, 1H); of 2.81 (t, 2H); 1,81 (dual. 2H); to 0.97 (t, 3H).

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Part C. 3-n-Pro saw-4-(phenylethynyl)imide evil-5-carboxaldehyde.

In a nitrogen atmosphere, was heated to 70oC solution containing 2.64 g of 4-iodine-2-n-propylamide evil-5-carboxaldehyde (0.01 M), 25 ml of dehydrated dimethylformamide, 2.5 ml of triethylamine, 1 g (0,001426 M) chloride bis(triphenylphosphine)palladium and 5 g (phenylethynyl)anti (0,017 M). The reaction mixture was stirred for 120 h, and then cooled. The precipitate was filtered and washed with methylene chloride and the filtrate evaporated under reduced pressure. The residue was dissolved in 200 ml of methylene chloride and was extracted with three portions of 10% HCl, 100 ml of the pH Value of the aqueous layer was adjusted to 10 with 50% sodium hydroxide solution, after which this layer was extracted with three portions of methylene chloride in 100 ml of Organic phase was dried over sodium sulfate and evaporated under reduced pressure. The result was obtained 0.56 g of 3-n-Pro saw-4-(phenylethynyl)imide evil-5-carboxaldehyde (0,0023 M, yield 23%).

Characteristics NMR (CDCl3): of 9.89 (s, 1H); by 8.22 (s, 1H), to 7.93 (m, 3H); 7,53 (m, 2H), 2,87 (t, 2H); to 1.87 (m, 2H); of 1.03 (t, 3H).

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Part D. Getting 4-phenyl ethinyl-3-n-propyl-1-[(2'-(1H-Tetra Zol-5-yl)biphenyl-4-yl)meth is 4-methyl bromide-2'-[N-triphenyl methyl-(1H-tetrazol-5-yl)] biphenyl by the procedure described in example 1, part D, and I, with the purpose of obtaining a product, the name of which is given above.

Characteristics NMR (CDCl3): 9,88 (s, 1H); 8,03 (m, 1H); EUR 7.57-7,27 (m, 8H); 7,17 (m, 2H); 7,01 (m, 2H); of 5.55 (s, 2H); 2,61 (t, 2H); to 1.75 (m, 2H); 0,99 (t, 3H).

In table. 1 shows compounds of General formula below, which can be obtained according to the method of example 2.

Example 27

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Part A. Obtain 4-(fu ran-2-yl)-2-n-propylamide evil-5-carboxaldehyde.

In a nitrogen atmosphere at room temperature was stirred solution containing 2.64 g of 4-iodine-3-n-propylamide evil-5-carboxaldehyde (0.01 M), 60 ml of toluene and 0.33 g (0,00029 M) tetranitroaniline palladium (O), which was gradually introduced a solution of 2.34 g of furan-2-elborno acid (0,0174 M) in 50 ml of ethanol. The reaction was continued under the conditions of mixing for 5 min, and then was gradually added 12 ml of a 2M solution of sodium carbonate. After implementing this solution, the reaction mixture was subjected to distillation of the solvent for 8 h, and then cooled. The reaction products were filtered, the filtrate evaporated under reduced pressure and the resulting residue was dissolved in 300 ml of methylene chloride, washed with two portions of saturated sodium chloride solution, 100 ml, ZAT is led in an alkaline (pH 10) 50% sodium hydroxide solution. Received basic aqueous layer was extracted with three portions of methylene chloride in 300 ml. Methylenechloride layer was obezvozhivani over sodium sulfate and evaporated under reduced pressure. Output 5-carboxaldehyde amounted to 0.34 g (0,00156 M).

Characteristics NMR (CDCl3): 10,14 (s, 1H); rate of 7.54 (s, 1H); 7,00 (d, 1H); 6,55 (m, 1H); and 2.79 (t, 2H); of 1.80 (m, 2H); of 1.02 (t, 3H).

According to the methods described in example 27, part a, have been obtained or can be obtained the following compounds (see table.2).

Part B. Obtain 4-(fu ran-2-yl)-2-n-propyl-1-[2'-(1H-Tetra Zol-5-yl)biphenyl-4-yl)methyl]imida evil-5-carboxaldehyde.

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4-(Furan-2-yl)-2-n-propylamide evil-5-carboxaldehyde was converted into a product that is specified in the header, using the techniques described in example 1, part D and I. the melting point of this product 129oC (decomp.).

Characteristics NMR (CDCl3): 10,15 (s, 1H); to 7.95 (d, 1H); at 7.55 (m, 2H); 7,38 (m, 2H); 7,10 (d, 2H); 6,98 (d, 2H); 6,85 (d, 1H), 6,45 (m, 1H); of 5.55 (s, 2H); to 2.55 (t, 2H); to 1.70 (m, 2H); of 0.91 (t, 3H).

The compounds specified in the examples table.3, can be obtained according to the methods described in example 27, using suitable starting materials.

The compounds listed in table.4, can be synthesized according to the methods described in examples 1, 2 Osho well-known specialist in this field.

Example 41

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Getting 2-n-butyl-4-phenyl thio-1-[(2'-(1H-tetrazol-5-yl)bi phenyl-4-yl)methyl]imida evil-5-carboxaldehyde.

To a freshly prepared solution of sodium methoxide in methyl alcohol containing 205 mg of sodium (8.9 M, 10 EQ) and 40 ml of methyl alcohol was added 590 mg of 2-n-BU Tyl-4-chloro-1-[(2'-n-triphenyl methyl-(1H-tetrazol-5 - yl)biphenyl-4-yl)methyl] -imidazole-5-carboxaldehyde (0,89 mm, 1 EQ) obtained as described in European patent application 89100144.8 published 7.19.89, and of 0.91 ml thiophenol (8.9 mm, 10 EQ). The resulting mixture is kept off the solvent during the night in a nitrogen atmosphere. Next, the solvents were removed in vacuo, and the residue was dissolved in 50 ml of water. The pH value was adjusted to 10-12 10h NaOH solution. Formed kauchukopodobnoe solid, representing a compound containing a protective group of TNT, was dissolved by adding 50 ml of ethyl ether. Then there was the separation of the layers and the aqueous layer was extracted with two portions of ethyl ether in 50 ml. Then the aqueous layer was extracted with six portions of ethyl acetate, 50 ml of an ethyl acetate layers were collected together, obezvozhivani using magnesium sulfate, and the solvent was removed in vacuum. As a result received the remainder, which is again the translation is dropped koutsokoumnis sediment containing the desired product, which was dissolved in 50 ml of ethyl acetate. Then spent the separation of the layers and the aqueous layer was extracted with two portions of ethyl acetate, 50 ml of an ethyl acetate layers were collected together, obezvozhivani using magnesium sulfate, and the solvent was removed in vacuum. In the received 200 mg of a white glassy substance. Crystallization from hot n-butyl chloride gave 142 mg of a white solid with a melting point 143,5-145,5oC.

Characteristics NMR (dimethylsulfoxide-d6): 9,82 (s, 1H); 7,80-to 7.61 (m, 2H); 7,58 (d, 1H, J=8 Hz); 7,52 (d, 1H, J=8 Hz); 7,45-7,20 (m, 5H); to 7.09 (d, 1H, J=8 Hz); 7.03 is (d, 2H, J=8 Hz); 5,62 (s, 2H); of 2.64 (t, 2H, J=7 Hz); 1.50 in (t, t, 1H, J=7,7 Hz); 1,25 (t of q, 2H, J=7,7 Hz); to 0.80 (t, 3H, J=7 Hz).

Analysis calculated for the formula C28N26N6OS(H2O)for 0.4: C 67,02; H 5,38; N X 16.75; S 6,39.

Found: C 66,90; H 5,20; N X 16.75; S 6,00.

Connection examples 42-49 table.5 can be synthesized using the methods described in example 41 and other examples of the present application, as well as in the European patent 89100144.8 published 19.07.89, or other methods well known to the specialist in this field.

Example 50

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Part A. Obtain 2-n-Pro saw-4-cyclobutylmethyl-5-hydroxy methyl-1-[(2'-(N-three is util)triphenylphosphine (0,0155 mm, 2 EQ) in 125 ml of tetrahydrofuran. To the suspension at room temperature was added to 41.4 ml of a 0.75 M solution hexamethyldisilazane potassium (0,031 mm, 4 EQ). Did the staining mixture in blood red. After 0.5 h, was added 5 g of 2-n-propyl-5-hydroxy methyl-1-[(2'-(N-triphenyl methyl-(1H-tetrazol-5-yl))bi phenyl-4-ylmethyl] imida evil-4-carboxaldehyde (7,75 mm, 1 EQ) in a mixture of a suspension in tetrahydrofuran. Over time the suspension became a yellow-orange. After 24 h the reaction was completed by adding a small amount of methyl alcohol with the purpose of rapid cooling, after which was added ethyl acetate and water. Then carried out the separation of the layers and washed the organic layer first two portions of water, and then one portion of brine. Next, the organic layer was obezvozhivani using magnesium sulfate and the solvent was removed in vacuo, and the residue was subjected to thin-layer chromatography in a mixture of pentane and ethyl acetate (ratio of these components 60:40) to 100% ethyl acetate. The result was 4.12 g (yield 78%) of a white substance with a melting point 181,5-182,5oC.

Characteristics NMR (dimethylsulfoxide-d6): d for 7.78 (m, 1H); to 7.61 (t, 1H, J= 7 Hz); rate of 7.54 (t, 1H, J=7 Hz); of 7.48-7,20 (m, 10H); 7,03 (d, 2H, J=7 Hz); of 6.96-6,70 (m, 8H); of 5.99 (s, 1H); to 5.13 (s, 2H); Analysis for the formula C45H42N6O(H2O)0,75: C. H. n

< / BR>
Part B. Obtain 2-n-Pro saw-4-cyclobutylmethyl-5-hydroxy methyl-1-[2-(1H-tetrazol-5-yl)bi phenyl-4-yl)methyl]imidazole.

Preparing a mixture of 1 g of 2-n-Pro saw-4-cyclobutylmethyl-5-hydroxy methyl-1-[2'-(N-triphenyl methyl-(1H-tetrazol-5-yl))bi phenyl-4-yl)methyl]-imidazole, 25 ml of methyl alcohol and 15 ml of tetrahydrofuran, which was stirred and boiled for 24 hours the Solvent was removed in vacuo and the residue was immediately subjected to thin-layer chromatography in a mixture of pentane with ethyl acetate (ratio of these components is 1:1) to 100% isopropyl alcohol and gradually to 100% ethyl alcohol to obtain 320 mg of a light yellow glassy substance.

Characteristics NMR (dimethylsulfoxide-d6): to 7.59 (d, 1H, J=7 Hz); rate of 7.54 (t, 1H, J=7 Hz); 7,46 (t, 1H, J=7 Hz); 7,42 (d, 1H, J=7 Hz); 7,06 (d, 2H, J= 7 Hz); 6.90 to (d, 2H, J=7 Hz); 5,97 (s, 1H); to 5.17 (s, 2H); or 4.31 (s, 2H); 3.04 from (m, 2H); 2,77 (m, 2H), 2,42 (t, 2H, J=7 Hz); of 1.97 (m, 2H); 1,53 (t of q, 2H, J=7,7 Hz); 0,86 (t, 3H, J=7 Hz).

Analysis for the formula C26H28N6O: C, H, n

The usefulness of the invention.

The hormone angiotensin II (AII) is causing various biological responses, such as compression of the vessels by stimulating existing cellular membrance with AII receptor, originally used ligand-receptor binding by the method, which was described by Glassman al. (Glossman et al. J. Biol. Chem. 1974, v.249, p.825), with some modifications. The reaction mixture contained adrenal cortical microsome assay (source receptor AII) in Tris-buffer solution containing 2 nm3H-AII in the presence of potential AII antagonist or without him. The mixture was subjected to ripening for 1 h at room temperature, and immediately upon completion of the reaction was carried out by rapid filtration and washing through teclmically filter. Hormone3H-AII associated with the receptor, captured on the filter was quantitatively determined by counting scintillations (flashes). Inhibitory concentration IC50potential antagonist to the hormone AII characterizing 50% replacement of all specifically related groups3H-AII, is a measure of the affinity of these compounds in relation to the AII receptor. Connections matching the present invention, the tested method binding, showed values IC50order 10-5M or less (see table.6).

Potential antihypertensive activity of the compounds conforming to the present invention can be demonstrated by natraceutical artery, see Kangana al. (Cangiano et al. J. Pharmacol. Exp. Ther. 1979, v.208, p.310). This operation increases the blood pressure due to increased production Repin, accompanied by increased levels of the hormone AII. Compounds were appointed tematicheskie at doses of 30 mg/kg was injected through a tube inserted into the jugular vein at a dose of 3 mg/kg. While continuously performed direct measurement of arterial blood pressure using a tube inserted into the carotid artery, and to write data applied to the pressure sensor and multi-chart recorder. Levels of blood pressure before the experiment was compared with the corresponding levels before treatment to establish protivogipertonicheskoe action of the tested compounds. Some compounds that meet present invention, showed intravenous activity at the dose of 3 mg/kg, and some activity in the appointment tematicheskie 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 from the impact zone in the body of warm-blooded jivotnogo introduction into the abdominal cavity. In order additions or exceptions, the drug can also assign tematicheskie (through the mouth).

Medications you can assign any conventional method suitable for use in combination with other drugs, representing both individual drugs and combinations of drugs. Drugs may be administered in pure form, but as a rule, together with a pharmaceutical carrier 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 assignment of the nature of the desired effect. Usually a daily dosage of active ingredient is 1-500 mg/day. Typically, to achieve the desired results rather 10-100 mg/day (once or several times per day). These dosage effective for the treatment of hypertension, t is Alenia, and also for adjusting the load on the heart by opening the blood 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 enter by injection in the form of a sterile liquid dosage.

Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic 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 krasivaya the preparation of injection and similar solutions, input 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 necessary, buffer substances. Suitable stabilizing agents are anti-oxidant agents, such as bisulfite or sodium sulfite, or ascorbic acid, alone or in combinations. In addition, the use of citric acid and its salts, and sodium ethylenediaminetetraacetate. Solutions for administration by injection may contain preserving additives, such as benzalkonium chloride, methyl - or propylparaben, chlorobutanol.

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

Used in the pharmaceutical dosage destination for compounds that meet present invention, is shown below.

The capsule.

Capsules soft gelatin.

Preparing 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 gelatino getting soft gelatin capsules containing 100 ml of the active ingredient. These capsules are washed and dried.

Tablets.

Many kinds of tablets are prepared according to the conventional technology, when the dosage is 100 mg of 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. 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) in an aqueous solution of propylene glycol. When you bring the volume up to the mark use special water for injection. The finished solution is sterilized.

Suspension.

For purposes tematicheskie (black active ingredient, 100 mg of sodium salt of carboxymethyl cellulose, 5 mg of sodium benzoate, 1 g arbitrage solution, U. S. P. as well as of 0.025 ml of vanillin.

The same kinds of dosages listed above can be used in the appointment of compounds conforming to the present invention, any of the 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 and methods of appointment are shown in table.7 and 8.

When used in conjunction with drug spit dose of AII blockers are usually the same as 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 possible that the connection meets the present invention will also be useful in the treatment of chronic renal failure.

1. Substituted imidazoles of General formula I

< / BR>
where R1the radical of the formula

< / BR>
Il; phenylalkyl in which Alchemilla portion contains 2 to 6 carbon atoms; 2 - or 3-furyl; biphenylyl; phenoxyphenyl; phenylthio; pyridylthio or 3-mercaptophenyl; methylthio;

R8-

< / BR>
< / BR>
R11H;

R13-

< / BR>
R16H;

R17H;

R31H;

X carbon-carbon single bond;

n 1 10;

r 1 2,

provided that R1is not in anthopology; R13is ortho - or metaprogram,

or their pharmaceutically acceptable salts.

2. Substituted imidazoles under item 1, characterized in that they possess antihypertensive activity.

3. Pharmaceutical composition having antihypertensive activity containing the active substance and a pharmaceutically suitable carrier, wherein the active substance contains a compound under item 1 or 2, taken in an effective amount.

4. The composition according to p. 3, characterized in that it further comprises a diuretic or non-steroidal anti-inflammatory agent.

 

Same patents:

The invention relates to a derivative of bis-benzo - or benzopyrano-piperidine, piperidylidene and piperazine, which are particularly useful as antagonists of platelet-activating factor and antihistamine, and their pharmaceutical compositions, methods of use of these derivatives and to the method of production thereof

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 heterocyclic compounds having angiotensin II antagonistic activity

The invention relates to compounds of the formula

< / BR>
and their pharmaceutically acceptable salts, in which:

R represents phenyl, substituted with 1-2 substituents, each independently from each other selected from halogen;

R1represents C1-4alkyl;

R2denotes H or C1-4alkyl; and

"Het", which are attached to adjacent carbon atom by a ring carbon atom, chosen from pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, "Het" optionally substituted C1-4the alkyl, C1-4alkoxy, halogen, CN, NH2or-NHCO2(C1-C4) alkyl

The invention relates to imidazo - annelirovaniya ISO - and heterocyclic compounds, method of their production and to the tools based on them

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 the field of synthesis of organic compounds and relates to new derivatives of imidazole, which are intermediate products in the synthesis of imidazole derivatives having valuable biological properties

The invention relates to a process for the preparation of 9-substituted derivatives of guanine General formula I:

< / BR>
where R is C1-C4-alkyl, does not necessarily substituted by one or more groups, or R is:

< / BR>
a benzyl, robotjam, 2-deoxyribosyl or (CH2)n-OR1where n is 1 or 2, and R1is CH2CH2OH or< / BR>
or their salts

The invention relates to a process for the preparation of 9-substituted derivatives of guanine General formula

(l) where R is a C1-C4-alkyl, optionally substituted by one or more hydroxyl groups, or R is

a benzyl, ribosom, 2-deoxyribosyl or (CH2)n-OR SIG1where n is 1 or 2, and R1is CH2CH2HE or CHor their salts

The invention relates to new derivatives of pyridinemethanol formula RNI where R1represents a hydrogen atom, a C1-C3-alkyl; R2is1-C4-haloalkyl; R3represents a halogen atom, trifluoromethyl; R4is1-C3-haloalkyl, the method of obtaining these compounds and insecticides containing these compounds as active ingredients

The invention relates to the field of organic chemistry and relates to a method of obtaining new derivatives of imidazole

The invention relates to methods of producing substituted imidazole derivatives and their non-toxic pharmaceutically acceptable acid additive salts
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