PL176171B1 - Trisubstituted biphenyls, method of obtaining sames and medicines containing them - Google Patents

Abstract

CLAIMS 1. Trisubstituted biphenyls of general formula I in which R1 denotes a carboxylic acid or a C1-C6-alkoxycarbonyl, R2 is an unbranched or branched group C1-C6-alkyl, R3 represents a chlorine and bromine fluorine group hydroxy, cyano, C1-C6-alkoxy, unbranched or branched C1-C6-alkyl, trifluoromethyl, trifluoromethoxy, carboxamide, carboxyl, C1-C6-alkoxycarbonyl or nitro and R4 is a tetrazolyl moiety, and their salts. PL 17βΤ7-Β B1 5. A method for producing trisubstituted biphenyls of formula Is a carboxy residue or a Ci-C6alkoxycarbonyl residue, r2 is unbranched or branched a C1-C6-alkyl group, R3 represents a fluorine, chlorine, bromine atom, hydroxy, cyano, C1-C6-alkoxy, unbranched or branched C 1 -C 6 alkyl group, trifluoromethyl group, trifluoromethoxy, carboxamide, carboxylic acid, Ci-C6-alkoxycarbonyl or nitro and R4 is the moiety or a tetrazolyl, characterized in that (1) a pyridone of the general formula 2, in which R © r2 are as defined above, is reacted, in an inert solvent in the presence of a base and optionally with by addition of a catalyst, with the general compound of formula 3, w where r3 is as defined above, R4 represents the remainder of the formula 8 and E is chlorine or bromine, then obtained the product cleaves the protective triphenylmethyl group into the known the method, and then the compound obtained is optionally carried out in salt.

Description

The present invention relates to trisubstituted biphenyls of the general formula, in which R ¹ represents a carboxyl residue or a C ¹ -C 6 -alkoxycarbonyl residue, R ² represents an unbranched or branched C 1 -C 6 -alkyl group, R ³ represents a fluorine, chlorine and bromine atom, a hydroxyl group, a cyano group , C1-CO-alkoxy, branched or unbranched CrCo-alkyl, trifluoromethyl, trifluoromethoxy, carboxamido, carboxyl, CrCo-alkoxycarbonyl or nitro and ^R4 represents tetrazolyl residue and salts thereof.

The trisubstituted biphenyls of the invention may exist as a salt. In general, salts with organic or inorganic bases are mentioned. Preferred salts in the context of the present invention are physiologically acceptable salts. Physiologically acceptable salts of the tri-substituted biphenyls are generally the metal and ammonium salts of the compounds of the invention. Particularly preferred are, for example, the lithium, sodium, potassium, magnesium or calcium salt, as well as the ammonium salts formed by ammonia or an organic amine, such as, for example, ethylamine, diethylamine or triethylamine, diethanolamine or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine or ethylene diamine. .

The compounds of the invention may exist as stereoisomers, either as enantiomers or as diastereomers. The invention therefore relates to both enantiomers and diastereomers and mixtures thereof. The racemic forms, like the diastereomers, can be separated into homogeneous stereoisomers in a known manner (cf. E.L. Eliel, Stereochemistry of Carbon Compound, McGraw Hill, 1962). Moreover, the formation of atropic isomers is also possible.

Compounds of the general formula I are preferred, in which R 1 is a carboxyl residue or a C 1 -C 4 alkoxycarbonyl residue, R 2 is an unbranched or branched C 1 -C 5 alkyl group, R 3 is a fluorine, chlorine, bromine, hydroxyl, cyano group, C 1 -C 5 - alkoxy, unbranched or branched C1-C4-alkyl, trifluoromethyl, trifluoromethoxy, carboxamide, carboxyl, Cp-C4-alkoxycarbonyl or nitro group and R4 is a tetrazolyl residue and salts thereof.

Particularly preferred are compounds of the general formula I in which R 1 is carboxyl, methoxycarbonyl or ethoxycarbonyl, R 2 is propyl, butyl or pentyl, R 3 is fluorine, chlorine, hydroxyl, cyano, methyl, methoxy, ethoxy, ethyl, trifluoromethyl , trifluoromethoxy, carboxamide, carboxylic, methoxycarbonyl, ethoxycarbonyl or nitro, and R4 is a tetrazolyl moiety and salts thereof.

The most preferred of the compounds of the invention is the compound 6-butyl-4-methoxycarbonyl-2-oxo-1 - [(3-fluoro-2'-tetrazol-5-yl-biphenyl-4-yl) -methyl] -1,2- dihydropyridine of formula 51, which is an extremely effective blood pressure lowering drug.

The invention further relates to a process for the preparation of compounds of general formula I in which all symbols have the above meanings, which consists in that (1) a pyridone of general formula 2 in which R1 and r2 are as defined above, is reacted in in an inert solvent in the presence of a base and optionally with the addition of a catalyst,

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^{-5.4 Ζ with a} compound of the general formula III, in which R is as defined above, R is the residue of formula 8 and E is chlorine or bromine, and the protective triphenylmethyl group is cleaved from the product obtained in a known manner with acids in in an organic solvent or in water, and the resulting compound is optionally salified.

In case R ¹ is an ester group, it can be saponified to the free acid group.

For the preparation of the particularly preferred 6-butyl-4-methoxycarbonyl-2-oxo1 - [(3-fluoro-2'-tetrazol-5-yl-biphenyl-4-yl) methyl] -1,2-dihydropyridine of the formula 51 The 6-butyl-4-methoxycarbonyl-2-oxo-1,2-dihydropyridine is reacted in an inert solvent in the presence of a base and optionally with the addition of a catalyst with 5- (4'-bromomethyl-3'-fluorobiphen-2-) yl) -N-triphenylmethyl-1H-tetrazole, the protective triphenylmethyl group is cleaved from the product obtained in a known manner.

The method according to the invention is illustrated by example in Scheme 1.

Suitable solvents for the process according to the invention are conventional organic solvents which do not convert under the reaction conditions. These preferably include ethers such as diethyl ether, dioxane, tetrahydrofuran, dimethoxyethane, or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum distillation fractions, or halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachethylene methane, dichloromethane. , trichlorethylene or chlorobenzene, or ethyl acetate, dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone, or nitromethane. It is also possible to use a mixture of the above solvents. Preferred solvents are tetrahydrofuran, acetone, dimethylformamide, and dimethoxyethane.

In general, inorganic or organic bases can be used as bases in the process according to the invention. These preferably include alkali metal hydroxides, such as, for example, lithium hydroxide, sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxides, such as, for example, barium hydroxide, alkali metal carbonates, such as, for example, sodium carbonate, potassium carbonate or cesium carbonate, alkaline earth metal carbonates, such as, for example, calcium carbonate, alkali metal or alkaline earth metal alcoholates or amides, such as, for example, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, or lithium diisopropylamide (LDA) , or organic amines r.trialkyl (C 1 -C 6) amines] such as triethylamine, or heterocyclic compounds such as

1,4-diazabicldo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), pyridine, diaminopyridine, methylpiperidine or morpholine. Alkali metals such as sodium or their hydrides such as sodium hydride can also be used as bases. The preferred bases are potassium carbonate, sodium hydride, potassium tert-butoxide, and cesium carbonate.

In general, in the process according to the invention, an amount of base is used in an amount of 0.05-10 moles, preferably 1-2 moles, based on 1 mole of the compound of formula 3.

The process according to the invention is generally carried out at a temperature of -100 ° C to + 100 ° C. Preferably from 0 ° C to 80 ° C.

In the process according to the invention, as a rule, atmospheric pressure is used, but it is also possible to use reduced or increased pressure (for example in the range from 0.05 to 0.5 MPa).

As a catalyst, as a rule, metal complexes such as nickel, palladium or platinum are used in the process according to the invention. Preferably palladium (O) complexes, such as palladium tetrakistriphenylphosphine, for example. Phase transfer catalysts such as, for example, tetra-n-butylammonium bromide or crown ether can also be used.

The cleavage of the triphenylmethyl group in the process according to the invention is carried out with acetic acid or trifluoroacetic acid and water or one of the above-mentioned alcohols, or with aqueous hydrochloric acid in the presence of acetone or also alcohol, or with a solution of hydrogen chloride in dioxane. Cleavage · is generally carried out at a temperature of from 0 ° C to 150 ° C, preferably from 20 ° C to 100 ° C, under atmospheric pressure.

Potassium iodide or sodium iodide, preferably sodium iodide, are suitable catalysts.

Suitable bases for the saponification of the ester are conventional inorganic bases. These are preferably alkali metal or alkaline earth metal hydroxides,

17 <5171 such as, for example, sodium hydroxide, potassium hydroxide or barium hydroxide, alkali metal carbonates such as sodium carbonate, potassium carbonate or sodium bicarbonate, or alkali metal alcoholates such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide or potassium tert.-butoxide. The introduction of sodium hydroxide or potassium hydroxide is especially preferred.

Suitable solvents for the saponification reaction are water or conventional organic solvents used in the saponification reaction. These preferably include alcohols such as methanol, ethanol, propanol, isopropanol or butanol, or ethers such as tetrahydrofuran or dioxane or dimethylformamide or dimethylsulfoxide. The use of alcohols such as methanol, ethanol, propanol or isopropanol is especially preferred. It is also possible to use a mixture of the solvents mentioned.

The saponification reaction can also optionally be carried out with acids, such as, for example, trifluoroacetic acid, acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, sulfuric acid or perchloric acid, preferably with trifluoroacetic acid. The saponification reaction is generally carried out at a temperature of from 0 ° C to + 100 ° C, preferably from + 20 ° C to + 80 ° C. As a rule, atmospheric pressure is used in the saponification reaction, but it is also possible to use reduced or increased pressure (for example in the range from 0.05 MPa to 0.5 MPa). The base is used for the saponification reaction in an amount generally of 1 to 3 moles, preferably 1 to 1.5 moles, based on 1 mole of ester. It is especially advantageous to use equimolar amounts of the reactants.

In the saponification of tert-butyl esters, acids are generally used, such as, for example, hydrochloric acid or trifluoroacetic acid, in the presence of one of the above-mentioned solvents and / or water or a mixture thereof, preferably with dioxane or tetrahydrofuran.

In part, compounds of general formula II are known and can be prepared according to known methods.

In part, compounds of general formula III are known or can be prepared according to known methods. ,

In the process according to the invention, usually atmospheric pressure is used, but it is also possible to use reduced or increased pressures (for example in the range of 0.05-0.5 MPa).

Compounds of the general formula 1 can also be prepared by a second method not falling within the scope of the invention and described herein for information purposes.

The method consists in the fact that the compound of general formula 4, in which R ¹ , R ² and R ³ are as defined above, and L is a typical leaving group, such as, for example, bromine, iodine, methanol, toluene, etc. The fluoro- or trifluoromethanesulfonyloxy, and preferably bromine, is reacted in an inert solvent in the presence of a base and a metal catalyst with a compound of general formula 5 where T is hydrogen or triphenylmethyl, and then in the case of free tetrazole (R ⁴ / T ) the triphenylmethyl group is cleaved with an acid in an organic solvent and / or in water, and in the case of a carboxylic acid (R 4 / R ¹ ), the corresponding ester is saponified and the compound optionally converted into a salt thereof with a base.

The above method can be illustrated, for example, in the scheme 2.

Suitable solvents for the above process are conventional organic solvents which do not convert under the reaction conditions. These preferably include ethers such as diethyl ether, dioxane, tetrahydrofuran, dimethoxyethane, or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum distillation fractions, or halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachethylene methane, dichloromethane. , trichlorethylene or chlorobenzene, or ethyl acetate, triethylamine, pyridine, dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone, or nitromethane. It is also possible to use a mixture of the above solvents. Preferred solvents are tetrahydrofuran, acetone, dimethylformamide, and dimethoxyethane. It is also possible to use a mixture of the above solvents with water.

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The above process is generally carried out at a temperature of from -20 ° C to + 150 ° C, preferably from + 40 ° C to + 100 ° C.

The catalysts and pressure in the above process are preferably used as in the process of the invention. Saponification is carried out analogously and, if appropriate, the compounds obtained are converted into salts. The compounds of formula IV can be prepared, inter alia, by reacting a compound of formula 6 with a compound of formula 7 wherein R * -R ³ and 1 are as defined above and U is halogen.

The above manufacturing methods are presented for explanation only. They do not limit the preparation of the compounds of general formula I according to the invention. Any modification of these methods can similarly be used in their manufacture.

The trisubstituted biphenyls according to the invention exhibit a valuable range of pharmacological effects. The compounds of the invention have a specific AII antagonist activity as they competitively inhibit the binding of angiotensin II by receptors. They suppress the effect of angiotensin II on vasoconstriction and on the stimulation of aldosterone secretion. Moreover, they have an inhibitory effect on the proliferation of smooth muscle cells. Therefore, they can be used in drugs to combat arterial hypertension and atherosclerosis. In addition, they can be used to treat coronary heart disease, heart failure, cerebral dysfunction, ischemic cerebral disease, peripheral blood flow disorders, renal and adrenal dysfunction, vascular and bronchospasm related respiratory diseases, sodium retention, and edema. .

Agonist-induced contraction inhibition studies

Rabbits of both sexes are stunned by a blow to the neck and either bled or put to sleep with nembutal (about 60-80 mg / kg, intravenously) and killed by opening the chest. An artery is removed from the chest, freed from adjacent connective tissue, cut into annular segments 1.5 mm wide, and each of them is aged at 37 ° C under an initial load of approximately 3.5 g in 10 ml of organ bath, using Krebs enriched with carbogen medium -Henseleite with the following composition: 119 mmolide NaCl; 2.5 mmol / l CaCl2 · 2H2O; 1.2 mmol / 1 KH2PO4; 10 mmol / l glucose; 4.8 mmol / L KCl; 1.4 mmol / L MgS O4 7 H2O and 25 mmol / L NaHCO3. The contraction is determined isometrically using the Statham UC-2 measuring cell with a bridge amplifier (ifd Miilheim or DSM Aalen) and using the AID transformer (system 570, Keithley, Munich) the data is translated into a digital system and estimated. Every hour, a curve showing the concentration dependence of the agonist effect (DWK) is made. 3 or 4 individual agonist concentration values introduced into the bath at 4-minute intervals are used to construct each DWK curve. After completion of the preparation of the DWK curve, elution cycles are carried out (16 times each time for about 5 s / min with the above-mentioned medium), followed by a 28-minute rest period (i.e. incubation period), during which the contraction usually reaches the value primary. The height reached in the typical run of the third DWK curve serves as a reference value in the further evaluation of the test compound, which is added to the bath in increasing concentration at the beginning of the incubation period as the successive DWK curves are prepared. Each ring of the artery is stimulated all day long by the same agonist.

Table A

Agonists and their standardized concentrations (volume used per dose is 100 μl)

KCl 22.7; 32.7; 42.7; 52.7 mmol / l 1 Noradrenaline 3 x ^10'9 ; 3 x 10 '⁸; 3 x W '⁷; 3 x 10 ' ⁶ g / ml Serotonin 10-8; 10'7; 10 '⁶; 10 ' ⁵ g / ml B-HT920 10'7; 10 ⁶ ; 10 ^ g / ml Methoxamine 10'7; 106; 10 ^ g / ml Angiotensin II 3 x 10 · ^9; 10 '⁸; 3 x 1θΛ 10 ^ ⁷ g / ml

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When calculating the IC50 value (concentration of test compound causing 50% inhibition), the effect of the third consecutive (submaximal) agonist concentration is included here.

The compounds of the invention inhibit angiotensin II-induced contraction of rabbit isolated artery in a dose-dependent range. Contractions caused by potassium dipolarization or by other agonists are not inhibited at all or only slightly inhibited under high concentration conditions.

Blood pressure measurement in rats given angiotensin II infusion

Male Wistar rats (Moellegaard, Copenhagen, Denmark) weighing 300-350 g are anesthetized with thiopental (100 mg / kg, intraperitoneally). Following the tracheotomy, an arterial blood pressure catheter is inserted into the femoral artery, an angiotensin II infusion catheter and a test compound administration catheter are inserted into the femoral vein. After the administration of pentolinium (5 mg / kg, intravenously), an infusion of angiotensin II (0.3 (mg / kg / min) is started. After the arterial blood pressure reaches a constant value, the test compound is administered either intravenously or orally in the form of a suspension or solution in 0.5% tylose Changes in arterial blood pressure under the influence of the compound are reported as mean ± SEM values.

Determination of efficacy in the prevention of hypertension in watchful hypertensive rats

The antihypertensive efficacy of orally administered compounds of the invention is determined in watchful rats by surgically induced unilateral renal artery stenosis. For this purpose, the right renal artery is narrowed with a silver clamp with a lumen of 0.18 mm. As a result of this form of hypertension, there is an increase in the level of plasma inactivation after the first six weeks after surgery. Measurement of the arterial blood pressure of the animal is made bloodlessly at specified intervals after administration of the test compound using a tail cuff. Various doses of the test compound dispersed in the tylose suspension are administered intragastrically (orally) via an esophageal gavage. The compounds of the invention, when administered at clinically relevant doses, reduce arterial blood pressure in hypertensive rats. Furthermore, in a concentration-dependent range, the compounds of the invention inhibit the specific binding of radioactive angiotensin II.

The interaction of the compounds according to the invention with the angiotensin II receptor on the membrane fractions of the (bovine) adrenal cortex.

Freshly collected and carefully freed from the core of the capsule adrenal cortex (NNR) (bovine) is comminuted in a sucrose solution (0.32 M) with the Ultra-Turrax machine (Janke and Kunkel, Staufen iB) into a low-fragmented membrane homogenate and in two centrifugation steps partially purify into membrane fractions. The receptor binding assay is carried out with partially purified bovine NNR membrane fractions, with radioactive angiotensin II, using a sample volume of 0.25 ml, containing 50-80 g of partially purified membrane fraction, 3-5 nM ³ H-angiotensin II, buffer solution (50 mM Tris, i.e., trihydroxymethylaminomethane, pH = 7.2), 5 mM MgCl2, and the test compound. After an incubation period of 60 minutes at room temperature, the unbound radioactive portion of the sample is separated with a moistened glass fiber filter (Whatman GF / C), and the radioactivity of the bound portion, after elution of the protein with an ice-cold buffer solution (50 mM Tris / HCl; pH = 7.4; 5% PEG 6000) is determined spectrophotometrically in a scintillation mixture. Analysis of direct experimental data using a computer program yields a Ki or IC50 value (Ki is the corrected IC50 for the level of radioactivity used; IC50 value is the concentration of the test compound that results in 50% inhibition of the specific binding of the radioligand).

Test for the inhibition of smooth muscle cell proliferation by the compounds of the invention.

To evaluate the effectiveness of compounds in preventing proliferation, smooth muscle cells isolated from the aorta of rats by the technique of mid-membrane explantation are used (R. Ross,

J. Cell. Biol. 50, 172, 1971). Cells are plated on suitable culture dishes, usually in 96-well plates, and grown for 2-3 days at 37 ° C in 5% CO2 in Medium

17 (5171

199 with 7.5% FCS, 7.5% NCS, 2mM L-glutamine, and 15mM Hepes; pH = 7.4. Then, by liberation from serum, cells are synchronized within 2-3 days and further stimulated to growth with the aid of serum or other factors. At the same time, the test compound is introduced. After 16-20 hours, 1 gCi of ³ H-thymidine is added, and after a further 4 hours, the incorporation of this substance into the TCA-precipitated cell DNA is determined.

To determine the IC50 value, the concentration of the active ingredient is calculated which causes, under conditions of sequential dilution of the active ingredient, the half-maximal inhibition of thymidine incorporation induced by 10% FCS. The results of the tests carried out with the active substances described in the examples given are summarized in Table 1 below.

Table 1

ANGREC 2 (*) AORTARAB 2 (**) Example no Ki IC50 Ki [mol / l] IC50 [mol / l] LII 2.0 E-09 9.3 E-10 LIII 2.0 E-09 9.6 E-10 LIV 8.0 E-09 4.4 E-09 LV 7.0 E-09 6.7 E-10 LVIII 2.0 E-08 1.6 E-09 LX 5.0 E-09 3.6 E-09 LXXIX 1.0 E-06 2.4 E-08 LXXX 9.0 E-09 4.8 E-10 LXXXI 5.0 E-09 1.2 E-09 Lxxxm 4.0 E-08 6.0 E-09 LXVIII 1.0 E-07 3.2 E-09 LXIX 8.0 E-08 2.1 E-09 LXX 7.0 E-07 1.1 E-07 LXXI 7.0 E-09 6.5E-10 LXXII 9.0 E-09 2.4 E-09 LXXIII 6.0 E-09 5.1 E-10 LXXIV 3.7 E-07 LXXV 4.0 E-07 2.0 E-08 LXXXIII 4.4 E-07

(*) - The results relate to the above-described study on the interaction of the compounds according to the invention with the angiotensin II receptor on membrane fractions of the adrenal cortex (bovine); the meaning of the abbreviation Ki was explained there. An explanation of the IC50 abbreviation is given in Table A.

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The new active substances can be converted in a known manner into conventional preparations, such as tablets, dragees, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using for this purpose inert, non-toxic pharmaceutically acceptable carriers or solvents: In these preparations, the concentration of therapeutically active substances is of the compounds should be from about 0.5% to 90% by weight based on the total weight of the mixture, that is, they should be present in an amount sufficient to permit freedom in the dosage administered.

The formulations are prepared, for example, by mixing the active ingredient with a solvent and / or the carrier, optionally with the use of emulsifiers and / or dispersants, where, for example, when water is used as an extender, an organic solvent can optionally be used as the solvent. auxiliary. Administration is in the usual manner, preferably orally or parenterally, especially linguistically or intravenously. In the case of parenteral administration, solutions of the active compound may be introduced with a suitable liquid carrier.

In order to achieve an effective result, it is generally preferred for intravenous administration to use an amount of from about 0.001 to 1 mg / kg, especially from about 0.01 to 0.5 mg / kg, body weight, and for oral administration, the dose should be from about 0 0.01 to 20 mg / kg, preferably 0.1 to 10 mg / kg body weight. In addition, it may optionally be desirable to deviate from the above amounts depending on body weight or the mode of administration, individual response to the drug and its form, and the time of administration or the dosing interval. In some cases it may turn out to be sufficient less than the above-mentioned minimum quantity, while in other cases it is necessary to exceed the above-mentioned maximum quantity. When using a larger amount, it may be desirable to divide it into several single doses administered throughout the day.

The following examples illustrate the preparation of the starting compounds and the preparation of the active compounds according to the invention.

Preparation of starting compounds

Example I N- (1-Hydroxy-2-methyl-prop-2-yl) -2-methoxy-benzoic acid amide of formula 9.

15.2 g (100 mmol) of 2-methoxy-benzoic acid are dissolved in 300 ml of dichloromethane and, at 0 ° C, mixed with 14.2 g (105 mmol) of monohydrate of the triazole salt of 1-hydroxy-benzoic acid and with 21.66 g (105 mmol) of N, N-dicyldohexylcarbodiimide. The suspension thus obtained is stirred for 0.5 hours at room temperature, cooled again to 0 ° C and mixed with a solution of 9.89 g (111 mmol) of 1-hydroxy-2-methyl-2-propylamine and 12.65 g (125 mmol) of triethylamine in 300 ml of dichloromethane. After 1 hour the reaction is complete. The reaction mixture was washed with 1M hydrochloric acid and saturated sodium bicarbonate solution, dehydrated over sodium sulfate and concentrated under reduced pressure. The crude product is mixed with petroleum ether, filtered, washed with solvent and dried under very low pressure.

Example II. 4,5-Dihydro-5,5-dimethyl-2- (2-methoxyphenyl) oxazole of formula 10.

At room temperature, 16.0 g (71.7 mmol) of the compound from Example 1 are mixed with 17.1 ml (283.4 mmol) of thionyl chloride, stirred for 3 hours, the excess of starting materials is evaporated off, the residue is stirred with 500 ml of ether. diethyl and filtered. The solid precipitate is dissolved in water, covered with diethyl ether and the corresponding base is liberated with 2 M aqueous sodium hydroxide solution. The aqueous phase is extracted three times with ethyl acetate, the combined organic phases are dehydrated over sodium sulphate, evaporated and freed from residual solvent under very low pressure.

Example III. 4,5-Dihydro-5,5-dimethyl-2- (3'-fluoro-4'-methyl-biphenyl-2-yl) oxazo of formula 11.

Under argon, 14.7 g (605.7 mmol) of magnesium turnings in 50 ml of tetrahydrofuran p.a. 117.7 g (623 mmol) of 4-bromo-2-fluoro-toluene are added while stirring in 500 ml of tetrahydrofuran p.a. After 2 hours at 35-40 ° C, a clear solution is formed to which a solution of 74.0 g (360.5 mmol) of the compound of Example 2 in 500 ml of tetrahydrofuran p.a. is added dropwise at room temperature. The mixture is stirred, initially with gentle cooling; within 16

176,171 hours at approximately 25 ° C. The solvent is then evaporated off, the crude product is washed at 10 ° C with 600 ml of ethyl acetate and 800 ml of saturated ammonium chloride solution, dehydrated over sodium sulphate and evaporated under reduced pressure. For purification, 600 ml of diethyl ether are added, the solidified residue is filtered off and the crude product is taken up into the aqueous phase by repeated extraction with 2 M hydrochloric acid. The aqueous phase is covered with diethyl ether, the pH is adjusted to 13 with an aqueous sodium hydroxide solution, extracted three times with diethyl ether, dehydrated over sodium sulphate, evaporated and the residual solvent removed under very low pressure.

Example IV. 2- (3-Fluoro-4-methylphenyl) -benzonitrile of formula 12.

97.0 g (343 mmol) of the compound of Example 3 are introduced into 500 ml of pyridine and at 0 ° C., 31.3 ml (343 mmol) of phosphorus oxychloride are added at 0 ° C. The system is slowly warmed up and finally refluxed for 1 hour. Then it is cooled to room temperature and diethyl ether and 1 M hydrochloric acid are added so that the pH of the aqueous phase is 1.5. The organic phase is washed three times with 1 M sulfuric acid over sulfate and freed of residual solvent under very low pressure.

Example 5 5- (3'-Fluoro-4'-methyl-biphenyl-2-yl) -1H-tetrazole of formula 13.

A mixture of 2.26 g (10.7 mmol) of the compound from Example 4, 3.48 g (53.6 mmol) of sodium azide and 7.37 g (53.6 mmol) of the compound from Example 4 is refluxed for 24 hours. ) triethylammonium chloride in 30 ml of dimethylformamide pa The system was then cooled, partitioned between diethyl ether and 1M sulfuric acid, the organic phase was washed with water, dehydrated over sodium sulfate and the solvent was evaporated. The crude product was mixed with toluene, filtered off and dried in vacuo to give 1.89 g (7.2 mmol) of product. The mother liquor was centrifuged and purified again as described above to give 0.43 g (1.7 mmol) of product.

Example VI. 5- (3-Fluoro-4-methyl-biphenyl-2-yl) -N-triphenylmethyl-1H-tetrazole of formula 14.

50.55 g (199.2 mmol) of the compound of Example 5 are stirred for 17 hours at room temperature, with 58.58 g (210.0 mmol) of triphenylchloromethane and 33.2 ml (239.0 mmol) of triethylamine in 700 ml of dichloromethane. The system is then washed once with water and once with 1 M aqueous citric acid, dehydrated over sodium sulphate, centrifuged and freed from residual solvent under very low pressure.

Example VII. 5- (4'-Bromomethyl-3 ^/ -fluoro-biphenyl-2-yl) -N-triphenylmethyl-1H-tetrazole of formula 15.

A mixture of 82.90 g (173.2 mmol) of the compound from Example 6, 30.84 g (173.2 mmol) of N-bromosuccinimide and 0.87 g (5.3 mmol) of the compound from Example 6 is refluxed for 6 hours. mmol) 'azobisisobutyronitrile (as a radical initiator) in 11 tetrachloromethane. The system is then cooled, the precipitated succinimide is filtered off, washed with tetrachloromethane, the filtrate is evaporated and the residue is dried under very low pressure.

Example VIII. 6-Butyl-4-methoxycarbonyl-2-oxo-1,2-dihydropyridine of formula 16.

To a suspension of 29.25 g (0.15 mol) of 6-butyl-2-oxo-1,2-dihydro-isonicotinic acid in 200 ml of methanol, 12.5 ml (0.17 mol) of thionyl chloride are added dropwise with ice cooling. and stirred overnight at room temperature. The mixture is concentrated to dryness and the residue is chromatographed on 450 g of silica gel (sieve number 230-400) with dichloromethane-dichloromethane: methanol = 10: 1. Colorless crystals with mp (Mp) 106 ° C crystallize out from dichloromethane, diethyl ether, petroleum ether.

Example IX. 6-Butyl-4-methoxycarbonyl-2-oxo-1 - {[3-fluoro-2 / - (N-triphenylmethyl-tetrazol-5-yl) -biphenyl-4-yl] methyl} -1,2-dihydropyridine formula 17.

61.1 g (0.188 mol) of cesium carbonate are introduced into a solution of 31.4 g (0.15 mol) of the compound from Example 8 in 600 ml of dimethoxyethane, stirred for 15 minutes at room temperature, and 104 g (0.18 mol) of ) of the compound of Example 7, is stirred overnight at room temperature, and then refluxed for 3 hours. The mixture was partitioned between 800 ml of water and 800 ml of ethyl acetate, the organic phase was washed with saturated saline, dehydrated over Na2SO4 and concentrated. Residue

176 171 in the system petroleum ether: ethyl acetate = 5: 1 - 1: 1 are filtered through 2 kg of silica gel (sieve number 230-400).

Example X. 4-Bromo-3-methylbenzyl alcohol of formula 19.

93 ml of a 1M solution of borane-THF complex in THF are added dropwise under argon at 0 ° C to a solution of 10 g (46.5 mmol) of 4-bromo-3-methylbenzoic acid in 100 ml of THF. The mixture is heated to 20 ° C and stirred at this temperature for 16 hours. Then the excess of the borane complex is decomposed by careful addition of water (until the evolution of hydrogen ceases), extracted twice with 250 ml of ethyl acetate, the combined organic phases are washed twice with 100 ml of saturated sodium bicarbonate solution, water and saturated sodium chloride solution each time, and dehydrated. over sodium sulfate and concentrated. 8 g (86% of theory) of crude compound are obtained which is used further without purification. Rf = 0.5 (petroleum ether: ethyl acetate = 2: 1).

Example XI. 4-bromo-2-methylbenzyl alcohol of formula 20.

In an analogous manner to that in Example 11, the title compound is prepared from 10 g (46.5 mmol) of 4-bromo-2-methyl-benzoic acid. 10 g (107% of theory) of crude product are obtained. Rf = 0.73 (petroleum ether: ethyl acetate = 2: 1).

Example XII. 3-Amino-6-methylbenzonitrile of formula 23.

A suspension of 8.11 g (50 mmol) of 6-methyl-3-nitrobenzonitrile and 0.81 g of 10% palladium on carbon in 50 ml of ethanol and 50 ml of ethyl acetate is hydrogenated for 1 hour at a pressure of 0.29 MPa. The catalyst was filtered off, the filtrate was concentrated and the residue was crystallized from diethyl ether / petroleum ether to give the title compound with a yield of 59.6% of theory, Mp = 88 ° C.

Example XIII. 3-Bromo-6-methyl-benzonitrile of formula 24.

15.2 g (0.22 mol) of sodium nitrite in 160 ml of concentrated sulfuric acid are heated at 70 ° C and the solution thus formed is added dropwise at 20-40 ° C to a solution of 26.4 g (0.2 mol) the compound of Example 12 in 400 ml of glacial acetic acid. A solution of 63.1 g (0.44 mol) of copper bromide (Cu ¹ ) in 400 ml of concentrated hydrobromic acid is added dropwise to this system at 10-20 ° C, the mixture is stirred for 0.5 hours, and 1 l of water is introduced, the precipitate formed is filtered off and washed with water. The precipitate is then suspended in dichloromethane and the insoluble fraction is filtered off. The filtrate was washed with saturated sodium chloride solution, dehydrated over sodium sulfate and concentrated to give 19.2 g (44.5% of theory) of the title compound. Rf = 0.31 (petroleum ether: dichloromethane = 1: 2).

Example XIV. 3-Bromo-6-bromomethyl-benzonitrile of formula 25.

A suspension of 19.1 g (97.4 mmol) of the compound from Example 13, 17.3 g (97.4 mmol) of N-bromosuccinimide and 0.2 g of azobisisobutyric acid nitrile is stirred at reflux temperature for 1 hour. 100 ml of carbon tetrachloride. The system was then filtered, the filtrate was concentrated to dryness, and the residue was recrystallized from methanol to give 7.7 g (28.7% of theory) of the title compound, Mp = 81 ° C.

Example XV. 3-Chloro-4-iodo-toluene of formula 28.

250 ml of concentrated hydrochloric acid and 75 g (0.53 mol) of 4-amino-3-chloro-toluene are added to 166 g of ice, and then a solution of 40.3 g (0.583 mol) of sodium nitrite in 170 ml is added dropwise at 0 ° C. water. The mixture is stirred for 15 minutes, filtered through glass wool and, together with the similarly prepared batch of 4-amino-3-chloro-toluene, the solution is cooled to -2 ° C and added dropwise to the solution kept at room temperature 455 g (2.74 mol) of potassium iodide in 11 of water. The system is stirred overnight, extracted three times with diethyl ether and the combined organic phases washed twice with dilute aqueous sodium hydroxide solution, twice with dilute sodium bisulfite solution and water. The solution was then dehydrated over sodium sulfate, filtered, concentrated and the residue distilled at 131.5 Pa through a Vigreux column. At a temperature of 70-85 ° C, 149 g (7% of theory) of the fraction are collected as a yellow oil. Rf = 0.57 (hexane: ethyl acetate = 9: 1).

Example XVI. 3-Chloro-4-iodo-benzyl bromide of formula 29.

A suspension of 40.4 g (160 mmol) of the compound of Example 15 in 400 ml of tetrachloromethane, 31.3 g (176 mmol) of N-bromosuccinimide and 2.63 g (16 mmol) of azobisisobutyronitrile ( AIBN), then the system is cooled, the precipitate is filtered off and washed with tetrachloromethane. The combined filtrates are concentrated and used crude further.

Example XVTI. 3-chloro-4-trifluoromethylsulfonyloxy-benzoic acid methyl ester of formula 30.

To a solution of 5.49 g (29.4 mmol) of 3-chloro-4-hydroxy-benzoic acid methyl ester in 15 ml of pyridine, 5.5 ml (33 mmol) of trifluoromethanesulfonic acid anhydride is slowly added dropwise at 0 ° C and the system is stirred with for 5 minutes at 0 ° C and 4 hours at room temperature. It is then partitioned between water and diethyl ether, the organic phase is washed successively with water, dilute hydrochloric acid, water and saturated sodium chloride solution, dehydrated over sodium sulfate and concentrated. The residue was chromatographed with methylene chloride on silica gel to give 8.93 g (95.2% of theory) of the title product as a light yellow, low viscous oil. Rf = 0.83 (hexane: ethyl acetate = 3: 1).

Example XVIII. 5- (2 ⁾ -Chloro-4 ⁾ -methoxycarbonyl-biphenyl-2-yl) -2-triphenylmethyl-1H-tetrazole of formula 31.

Argon is purged through a solution of 1.00 g (3.14 mmol) of the compound from Example 17 in 50 ml of toluene, and 1.68 mg (0.14 mmol) of Pd [P (C6Hs) 3] 4.80 ml of methanol, 1.83 g (3.77 mmol) of 2- (N-triphenylmethyl-tetrazol-5-yl) -phenylboronic acid and a solution of 333 mg (3.14 mmol) of sodium carbonate in 4 ml of degassed water and stirring the emulsion thus formed overnight at 100 ° C. C. The same amount of catalyst is then added and the reaction is complete for a further 2.5 hours at 100 ° C., which results in complete conversion. The system was partitioned between water and ethyl acetate, the organic phase was washed with dilute sodium carbonate solution and saturated sodium chloride solution, dehydrated over sodium sulfate, concentrated and the residue was chromatographed on silica gel with hexane: ethyl acetate = 10: 1. 10.1 g (57.9% of theory) of a light yellow solid are obtained, Rf = 0.46 (hexane: ethyl acetate = 3: 1).

Example XIX. 5- (2'-Chloro-4'-hydroxymethyl-biphenyl-2-yl) -triphenylmethyl-1H-tetrazole of formula 32.

A solution of 22.0 g (39.6 mmol) of the compound from Example 18 in 180 ml of THF is mixed with 1.27 g (39.6 mmol) of methanol and 1.29 g (59.4 mmol) of lithium borohydride, followed by stirring. , it is heated for 30 minutes at room temperature and for 1 hour under reflux. A further 0.13 g (20 mmol) of methanol are then introduced and the reaction is stirred for 1 hour at reflux to complete the reaction. The reaction mixture is concentrated, the residue is taken up in 200 ml of methylene chloride and, under a vigorous stream of argon, with an ice bath, 100 ml of 1N potassium bisulfate solution are slowly added. The phases are separated and the aqueous phase is extracted with methylene chloride. The combined organic phases were washed with saturated sodium chloride solution, dehydrated over sodium sulfate and concentrated to give 20.5 g (98.19% of theory) of product as white crystals, Mp = 18.6-187 ° C (with decomposition). R f = 0.15 (hexane: ethyl acetate = 3: 1).

Example XX. 5- (4'-Bromomethyl-2'-chloro-biphenyl-2-yl) -2-triphenylmethyl-1H-tetrazole of formula 33.

To a solution of 11.2 g (42.5 mmol) of triphenylphosphine in 100 ml of methylene chloride is added dropwise under argon using an ice bath, first 79 g (42.5 mmol) of bromine and then

20.4 g of the compound of Example 19 in 300 ml of methylene chloride. The mixture is stirred for 1 hour at room temperature, filtered through silica gel and eluted with methylene chloride. The filtrate was concentrated and the residue was extracted warm with hexane to give 15.8 g (6.8% of theory) of product as white crystals, Mp = 15-20 ° C. Rf = 0.40 (hexane: ethyl acetate = 3: 1).

Example XXI. 2-hydroxy-5-methoxycarbonylbenzaldehyde oxime of formula 34.

To a solution of 80.5 g (0.45 mol) of 2-hydroxy-5-methoxycarbonylbenzaldehyde in 300 ml of methanol, a solution of 8.0 g (0.83 mol) of sodium acetate and 8.0 g (0.98 mol) of ) hydroxylamine hydrochloride in 300 ml of water. The mixture is stirred for 2 hours at 25 ° C, the precipitated product is filtered off, washed with water and dried under reduced pressure over phosphorus pentoxide. 70.4 g (80.7% of theory) of the title compound with a Mp = 155 DEG C. are obtained.

Example XXII. 2-Acetoxy-5-methoxycarboryl-berzonitrile of formula 35.

70.3 g (0.36 mol) of the compound of Example 21 are stirred for 1.5 hours at reflux temperature in 0.5 l of acetic anhydride, then the system is concentrated to dryness, the residue is dissolved in dichloromethane and petroleum ether is added. . As a result, the title compound crystallizes out (89.7% of theory) with Mp = 98 ° C.

Example XXIII. 2-Hydroxy-5-methoxycarbonylbenzonitrile of formula 36.

A suspension of 70.6 g (0.32 mol) of the compound of Example 22 and 3.48 g (0.06 mol) of sodium methoxide in 0.5 L of methanol was heated to reflux for 3 hours and then to reflux. At 25 ° C, the pH is adjusted to 6.5 with 1N hydrochloric acid. The system is concentrated under reduced pressure, the residue is taken up in dichloromethane, washed with saturated sodium chloride solution, the organic phase is dried over sodium sulfate, concentrated and crystallized from diethyl ether / petroleum ether. The product with Mp = 193 ° C is obtained in 98% of theory.

Example XXIV. 3-Cyano-4-trifluoromethylsulfonyloxy-benzoic acid methyl ester of formula 37.

In an analogous manner to Example XXVII, 98.2 g (100% of theory) of the compound mentioned in the title are obtained from 55.8 g (0.32 mol) of the compound of Example 21. Rf = 0.6 (petroleum ether: ethyl acetate = 2: 1).

Example XXV. 5- (2'-Cyano-4'-methoxycarbonyl-biphenyl-2-yl) -2-triphenyl-1H-tetrazole of formula 38.

In the same manner as in Example 18, from 3.0 g (10 mmol) of the compound of Example 24, 1.4 g (26% of theory) of the title compound are obtained with Mp = 220-240 ° C (with decomposition).

Example XXVI. 5- (2'-Cyaro-4'-hydroxymethyl-biphenyl-2-yl) -2-triphenylmethyl-1H-tetrazole of formula 39.

Analogously to Example 19, from 410 mg of the compound of Example 25, 254 mg (64.4% of theory) of the title compound with Mp = 208 ° C are obtained.

Example XXVII. 5- (4'-Bromomethyl-2'-cyro-biferyl-2-yl) -2-triphenylmethyl-1H-tetrazole of formula 40.

In an analogous manner to Example 20, 577 mg (2.2 mmol) of the compound of Example 25 are obtained, 588 mg (50.5% of theory) of the title compound with Mp = 194 ° C.

Example XXVIII. Trifluoromethanesulfonic acid 4-formyl-3-methoxyphenyl ester of formula 41.

Analogously to Example 17, 15.2 g (0.1 mol) of 2-methoxy-4-hydroxy-benzaldehyde and 31 g (0.11 mol) of trifluoromethanesulfonic acid anhydride are obtained from 15.8 g (59% of theory) of the mentioned in the title of the union. Rf = 0.38 (petroleum ether: ethyl acetate = 20: 1).

Example XXIX. Trifluoromethanesulfonic acid, 2-methoxy-4-methylphenyl ester of formula 42.

In an analogous manner to Example 17, 13.8 g (0.1 mol) of 2-methoxy-4-methylphenol and 31 g (0.11 mol) of trifluoromethanesulfonic acid anhydride are obtained, 26.5 g (98% of theory) mentioned in the title relationship. Rf = 0.76 (petroleum ether: ethyl acetate = 3: 1).

Example XXX. N-triphenylmethyl-5- [2- (4'-formyl-3-methoxybiferyl)] tetrazole of formula 43.

In an analogous manner to Example 18, from 2.46 g (10 mol) of the compound of Example 25, 3.1 g (56% of theory) of the compound mentioned in the title are obtained. Rf = 0.44 (petroleum ether: ethyl acetate = 5: 1).

Example XXXI. N-triphenylmethyl-5- [2- (2'-methoxy-4'-methylbiphenyl) tetrazole formula 44.

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In an analogous manner to Example 18, from 2.0 g (7.4 mmol) of the compound of Example 21 are obtained 1.75 g (47% of theory) of the named compound. Rf = 0.48 (petroleum ether: ethyl acetate = 5: 1).

Example XXXII. N-triphenylmethyl-5- [2- (4'-hydroxymethyl-3'-methoxybiphenyl)] tetrazole of formula 45.

A solution of 15.9 g (30.5 mmol) of the compound of Example XXX in 450 ml of anhydrous THF at 0 ° C under argon is added dropwise to 9.14 ml (9.14 mmol) of a 1 M solution of lithium aluminum hydride in THF. Then the cooling bath is removed, the system is stirred for 30 minutes at 20 ° C, 50 ml of water and 30 ml of 15% aqueous sodium hydroxide solution are added and the solvent is evaporated off under reduced pressure. The residue is taken up in a dichloromethane / water mixture, the aqueous phase is extracted twice with dichloromethane, the combined organic phases are washed twice with saturated sodium chloride solution, dried over sodium sulphate and concentrated. The residue is purified on silica gel using mixtures petroleum ether: ethyl acetate = 10: 1.5: 1.3: 1. and 1: 1. 11.5 g (72% of theory) of the title compound are obtained. Rf = 0.2 (petroleum ether: ethyl acetate = 3: 1).

Example XXXIII. N-triphenylmethyl-5- [2- (4'-bromomethyl-3'-methoxybiphenyl)] tetrazole of formula 46.

To a solution of 11.5 g (21.8 mmol) of the compound from Example 31 in 42 ml of diethyl ether, 6.2 g (23 mmol) of phosphorus tribromide are added dropwise at 0 ° C, and then stirred at 0 ° C for 1 hour. The reaction mixture was poured into ice-water, extracted three times with ethyl acetate, the combined organic phases were washed twice with saturated sodium bicarbonate solution, anhydrous over sodium sulfate and concentrated. The residue is used further without further purification. 8 g (62% of theory) of crude product are obtained. Rf = 0.56 (petroleum ether: ethyl acetate = 5: 1).

Example XXXIV. N-triphenylmethyl-5- [2- (4'-bromomethyl-2'-methoxybiphenyl)] tetrazole of formula 47..

In an analogous manner to Example 7, 7.73 g (15.2 mmol) of the compound of Example 31 are obtained from 6.57 g (74% of theory) of the title compound. Rf = 0.41 (petroleum ether: ethyl acetate = 10: 1).

Example XXXV. 6-Butyl-4-methoxycarbonyl-2-oxo-1 - {[2-chloiO-2 '- (N-triphenylmethyl-tetrazol-5-yl) -biphenyl-4-yl] -methyl} -1,2-dihydropyridine formula 48.

In a similar manner to Example 9, 6.11 g (29.2 mmol) of the compound from Example 8 and 15.7 g (26.5 mmol) of the compound from Example 20 are obtained 6.60 g (34.6% yield). theoretical) mentioned in the title of the compound. Rf = 0.35 (hexane: ethyl acetate = 3: 1).

The compounds of general formula 49, shown in Table 2, are obtained analogously to Example 9.

Table 2

Example No. R ³ R ³ ' Rf XXXVI H. CN 0.35 (cyclohexene: ethyl acetate = 10: 1) XXXVII OCH3 H. 0.46 (petroleum ether: ethyl acetate = 1: 1) XXXVIII H. OCH3 0.39 (petroleum ether: ethyl acetate = 1: 1)

Example XXXIX. 6-Butyl-4-methoxycarbonyl-2-oxo-1 - {[3-chloro-2 '- (N-triphenylmethyl-tetrazol-5-yl) -biphenyl-4-yl] methyl} -1,2-dihydropyridine formula 50.

In the manner analogous to that in Example 25, 3.44 g (41% of theory) of the title compound were obtained. Rf = 0.23 (ethyl acetate: petroleum ether = 1: 3).

The compounds of general formula 49, shown in Table 3, are obtained analogously to Example XXXV.

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Table 3

Example No. R ³ R ³ ' Rf XL NO2 H. 0.12 (hexane: ethyl acetate = 3: 1) XLI H. NO2 0.27 (hexane: ethyl acetate = 2: 1) XLII H. CH3 0.63 (toluene: ethyl acetate: glacial acetic acid = 20: 20: 1)

Manufacturing of active substances

Example XLIII. 6-Butyl-4-methoxycarbonyl-2-oxo-1 - [(3-fluoro-2'-tetrazol-5-ylbiphenyl-4-yl) -methyl] -1,2-dihydroxypyridine of formula 51.

A solution of 3.0 (4.2 mmol) of the compound from Example 9 in 40 ml of acetone is mixed with 0.4 ml of 37% hydrochloric acid at room temperature for 30 minutes and then heated for about 1 minute in a water bath. After the addition of a further 0.4 ml of 37% hydrochloric acid, the process was repeated. The system is then concentrated to dryness and the residue is chromatographed on 90 g of silica gel (sieve number 230-400) with a mixture of dichloromethane. Methanol = 50: 1 - 20: 1. 1.6 g (81% of theory) of the title compound are obtained. Rf = 0.49 (toluene: ethyl acetate: glacial acetic acid = 10:30: 1).

Example XLIV. 6-Butyl-4-methoxycarbonyl-2-oxo - {[3-methoxy-2 '- (tetrazol-5-yl) -biphenyl-4-yl] -methyl} -1,2-dihydroxypyridines of formula 52.

In an analogous manner to Example XLIII, from 435 mg (0.61 mmol) of the compound of Example XXXVII, 162 mg (56% of theory) of the named compound are obtained. Rf = 0.33 (toluene: ethyl acetate: glacial acetic acid = 20: 20: 1).

Example XLV. 6-Butyl-4-methoxycarbonyl-2-oxo-1- {[2-methoxy-2 '- (tetrazol-5-yl) -biphenyl-4-yl] -methyl} -1,2-dihydropyridine of formula 53.

In an analogous manner to Example XLH1, 740 mg (1.03 mmol) of the compound of Example XXXVE0 [455 mg (93% of theory) of the title compound are obtained. Rf = 0.28 (toluene: ethyl acetate: glacial acetic acid = 20: 20: 1).

Example XLVI. 6-Butyl-4-methocarbonyl-2-oxo-1 - {[2-methyl-2 '- (tetrazol-5-yl) -biphenyl-4-yl] -methyl} -1,2-dihydroxypyridine of formula 54.

Analogously to Example XLH1, 513 mg (79% of theory) of the title compound are obtained from 1 g (1.42 mmol) of the compound of Example XLII. Rf = 0.11 (toluene: ethyl acetate: glacial acetic acid = 30: 20: 1).

Example XLVII. 6-Butyl-4-methoxycarbonyl-2-oxo-1 - {[2-cyano-2 '- (tetrazol-5-yl) -biphenyl-4-yl] -methyl} -1,2-dihydropyridine of formula 55.

In an analogous manner to Example XLIH, from 1.0 g (1.13 mmol) of the compound of Example XXXVI, 679 mg (91.1% of theory) of the title compound are obtained with Mp = 210-215 ° C (with decomposition).

Example XLVDL 6-Butyl-4-methoxycarbonyl-2-oxo-1 - {[3-chloro-2 '- (tetrazol-5-yl) -biphenyl-4-yl] -methyl} -1,2-dihydropyridine of the formula 56.

Analogously to Example XLIIII, from 3.4 g (4.7 mmol) of the compound of Example XXXIX 1.7 g (75% of theory) of the named compound are obtained. Rf = 0.25 (dichloromethane: methanol = 10: 1).

Example XLIX. 6-Butyl-4-methoxycarbonyl-2-oxo-1- {[2-chloro-2 '- (tetrazol-5-yl) -biphenyl-4-yl] -methyl} -1,2-dihydropyridine of formula 57.

In an analogous manner to Example XLIII, 115 mg (44% of theory) of the compound mentioned in the title are obtained from 394 mg (0.55 mmol) of the compound of Example XXXV. Rf = 0.29 (dichloromethane-methanol = 20: 1).

Example L. 6-Butyl-4-methoxycarbonyl-2-oxo-1 - {[3-nitro-2 '- (tetrazol-5-yl) -biphenyl-4-yl] -methyl} -1,2-dihydropyridine formula 58.

In an analogous manner to Example XLIII, from 390 mg (0.53 mol) of the compound from Example XL are obtained 135 mg (52% of theory) of the named compound. Rf = 0.28 (dichloromethane: methanol = 10: 1).

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Example LI. 6-Butyl-4-methoxycarbonyl-2-oxo-1 - {[2-nitro-2 '- (tetrazol-5-yl) -biphenyl-4-yl] -methyl} -1,2-dihydropyridine of formula 59.

In an analogous manner to Example XLIII, from 790 mg (1.1 mmol) of the compound of Example XLI, 296 mg (56% of theory) of the title compound are obtained. 'Rf = 0.29 (dichloromethane: methanol = 10: 1). The compounds of general formula 60, shown in Table 4, are obtained analogously to Example XLIII.

Table 4

Example No. R ¹ R ² R ³ Form LII CO2H C4H9 3-F acid LIII CO2H C4H9 2-Cl acid LIV CO2H C4H9 3-Cl acid LV CO7C2H 5 C4H9 2-Me acid

Data illustrating the effects of the above compounds are given in Table 1 above. Example LVI. 6-Butyl-4-carboxy-2-oxo-1 - {[3'-fluoro-2 '- (tetrazol-5-yl) -biphenyl-4-yl] -methyl} -1,2-dihydropyridine of formula 61.

The above compound was prepared analogously to Example XLH [. 219 mg (22% of theory) of the title compound are obtained. Rf = 0.16 (toluene: ethyl acetate: glacial acetic acid = 10:30: 1). The compounds of general formula 62, shown in Table 5, are obtained analogously to Example XLIII.

Table 5

! Example No. R ² R ⁶ R ⁷ [M + H] ⁺ Rf LVII CH3- (CH2) 3- -CN H. 0.23 (B) LVIII CH3- (CH2) 3- -CH3 H. 0.24 (A) LEX CH3- (CH2) 3- H. F. 0.22 (B) LX CH3- (CH2) 4- F. H. 462 0.66 (A)

A - toluene: ethyl acetate: glacial acetic acid = 10: 30: 1 B - dichloromethane: methanol: glacial acetic acid = 10: 1: 0.3

Example LXI. 6-Butyl-4-methoxycarbonyl-2-oxo-1 - {[2-methoxycarbonyl-2 '- (tetrazol-5-yl) -biphenyl-4-yl] -methyl} -1,2-dihydropyridine of formula 63.

The above compound is prepared analogously to Example XLIII. 131 mg (74.6% of theory) of the title compound are obtained. Rf = 0.54 (dichloromethane: methanol = 5: 1).

The compounds of general formula 64 shown in Table 6 are obtained analogously to Example XLIH.

Table 6

Example No. R ³ r3 ' Rf LXII H. F. 0.40 (dichloromethane: methanol = 10: 1) LXIII COOCH3 H. 0.50 (dichloromethane: methanol: glacial acetic acid = 100: 10: 3) LXIV CN H. 0.38 (dichloromethane: methanol = 5: 1) LXV F. H. 0.49 (toluene: ethyl acetate: glacial acetic acid = 10: 30: 1) LXVI CH3 H. 0.49 (toluene: ethyl acetate: glacial acetic acid = 20: 20: 1)

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The following compounds were obtained analogously to Example XLHI: Example LXVH. tetrazol-5-yl) -biphenyl-4-yl] -methyl} -1,2-dihydropyridine of formula 8-Butyl'-methoxycarbonyl'-oxo-I-tetrazol-5-yl] -methyl.

58.6 mg (79.7% of theory) of the title compound are obtained.

Rf = 0.2 (ethyl acetate: methanol: water = 100: 15: 5).

Example LXVIII. 8-Biityl-4-carboxy-2-oxo-1 - {[2-carboxy-2 '- (tetrazol-5-yl) -biphenyl-4-yl] -methyl} -1,2-dihydropyridine of formula 9.

204 mg (37.4% of theory) of the title compound are obtained.

Rf = 0.10 (dichloromethane: methanol: acetic acid = 100: 10: 5).

Example LXIX. 1-Butyl-4-carboxy-2-oxo-1 - {[2-aminocarbonyl-2 '- (tetrazol-5-yl) -biphenyl-4-yl] -methyl} -1,2-dihydropyridine of formula 70.

Data illustrating the effect of this compound are presented in Table 1 above. Example LXX. t-butyl-4-carboxy-2-oxo-1 - {[3-methoxy-2 '- (tetrazol-5-yl) -biphenyl-4-yl] -methyl} -1,2-dihydropyridine of formula 71.

59 mg (45% of theory) of the title compound are obtained.

Rf = 0.17 (toluene: ethyl acetate: glacial acetic acid ^; = 20: 20: 1).

Example LXXI. t-Butyl'-carboxy'-oxo-l-t'-methoxy-tetrazol''-ylF-biphenyl-4-yl] -methyl} -1,2-dihydropyridine of formula 72.

3-3 mg (95% of theory) of the title compound are obtained.

Rf = 0.11 (toluene: ethyl acetate: glacial acetic acid = 10:30: 1).

Example LXXII. 8-Buty'l-4-carboxy-2-oxo-1 - {[3-methyl-2 '- (tetrazol-5-yl) -biphenyl-4-yl] -methyl} -1,2-dihydropyridine of the formula 73.

38.6 mg (84% of theory) of the title compound are obtained.

Rf = 0.17 (toluene: ethyl acetate: glacial acetic acid = 10:30: 1).

Example LXXIII. 1-Butyl-4-carboxy-2-oxo-1 - {[2-cyano-2 '- (tetrazol-5-yl) -biphenyl-4-yl] -methyl} -1,2-dihydropyridine of formula 74.

221 mg (97.2% of theory) of the title compound are obtained.

Rf = 0.22 (dichloromethane: methanol: glacial acetic acid = 100: 10: 3).

Example LXXIV. 1-Butyl-4-carboxy-2-oxo-1 - {[3-carboxymethyl-2 '- (tetrazol-5-yl) -biphenyl-4-yl] -methyl} -1,2-dihydropyridine of formula 18.

57 mg (6% of theory) of the title compound are obtained.

Rf = 0.26 (dichloromethane: methanol: glacial acetic acid = 100: 10: 3).

Example LXXV. 1-Butyl 1 -carboxy-2 -oxo-1 -6-cyano-4-tetrazol-1 -ylF-biphenyl-4-yl] -methyl} -1,2-dihydropyridine 21.

1.4 mg (100% of theory) of the title compound are obtained.

Rf = 0.23 (dichloromethane: methanol: glacial acetic acid = 1θ0: 10: 3).

Example LXXVI. 1-Butyl-4-methoxycarbonyl-2-oxo-1 - {[3-aminocarbonyl-2 '(tetrazol-5-yl) -biphenyl-4-yl] -methyl} -1,2-dihydropyridine of the formula 2-6.

472 mg (47% of theory) of the title compound are obtained.

Rf = 0.55 (dichloromethane: methanol: glacial acetic acid = 100: 10: 3).

Example LXXVII. 1-Butyl-4-kai'boxy-2-oxo-1- {[3-carboxy-2 '- (tetrazol-5-yl) -b and phenyl-4-yl] -methyl} -1,2- dihydropyridine of formula 27.

423 mg (44.9% of theory) of the title compound are obtained.

Rf = 0.11 (dichloromethane: methanol: glacial acetic acid = 100: 10: 3).

Example LXXVIH. 1-Butyl-4-methoxycarbonyl-2-oxo-1- {[2-aminocarbonyl-2 ^/ - (tetrazol-5-yl) -bipheny-4-yl] -methyl} -2-dihydropyridine, potassium salt of formula at 5.

A solution of 400 mg (0.82 mmol) of the compound of Example LXVIII in tetrahydrofuran is mixed with 1.644 ml (0.82 mmol) of 0.5N potassium hydrogen carbonate solution, diluted with 10 ml of water, tetrahydrofuran is distilled off under reduced pressure and the aqueous product solution is dried. on the way of freezing. 399 mg (92.5% of theory) of the title compound are obtained. MS (FAB): 487 (M + H), 525 (M + K + H).

The compounds of general formula VI, shown in Table 7, are obtained analogously to Example LXXVIH.

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Table 7

Example No. R ³ r3 ' R LXXIX H. CN K. LXXX CN H. K. LXXXI F. H. K.

Data illustrating the effects of the above compounds are summarized in Table 1 above

Example LXXXH. 6-Butyl-4-carboxy-2-oxo-1 - {[2-aminocarbonyl-2 '- (tetrazol-5-yl) -biphenyl-4-yl] -methyl} -1,2-dihydropyridine dipotassium salt of the formula 68.

A solution of 100 mg (0.2 mmol) of the compound of Example LXVII in 7 ml of tetrahydrofuran and 421 ml (0.421 mmol) of 1N potassium hydroxide solution is stirred for 4 hours at 20 ° C, diluted with 10 ml of water, the tetrahydrofuran is distilled off under reduced pressure and the aqueous product solution was freeze-dried. 103 mg (91.1% of theory) of the title compound are obtained. Rf = 0.15 (dichloromethane: methanol: acetic acid = 100: 10: 3).

Example LXXXH [. 6-Butyl-4-carboxy-2-oxo-1- {[3-aminocarbonyl-2 '- (tetrazol-5-yl) -biphenyl-4-yl] -methyl} -1,2-dihydropyridine disodium salt of the formula 22.

A solution of 134 mg (0.28 mmol) of the compound of Example No.XXVI and 541 g (0.54 mmol) of a 1N aqueous sodium hydroxide solution in 4 ml of tetrahydrofuran is stirred for 1 hour at 20 ° C, diluted with 10 ml of water, is concentrated and the remaining aqueous solution is freeze-dried. 142 mg (99.6% of theory) of the title compound are obtained. MS (FAB): 495 (M + Na) 51 &lt; + &gt; (M + 2Na-H), 539 (M + 3Na-2H).

176 171

176 171

Br-CH ₂

CO2CH3

Dimethoxyethane (DME)

Cs ₂ CO ₃

JL 1 nn _rlril ,

H ₃ C- (CH ₂ ) ₃ ^xk N '^ O ^{C, C} 6 ^h 5> 3

SCHEME 1 (1)

176 171

Acetone

HĆl * every ₂ ch ₃ h ₃ c- (ch ₂ ) ₃

SCHEME 1 (2)

Na ₂ C0 ₃ , DME, EtOH.t ^ O Tetrakis (triphenylphosphine) palladium

SCHEME 2

176 171

MODEL 1

PATTERN 5 PATTERN 6

176 171

AOS ~ ^{C (C} 6 ^H 5 ⁾ 3 MODEL 8

MODEL 10

MODEL 13

176 171

PATTERN 14

Br N-jVC (C ₆ H ₅ ) ₃

L nUnh

MODEL 15

176 171

MODEL 20

MODEL 22

NH ₂ Br

PATTERN 23 PATTERN 24

NC Br

MODEL 25

MODEL 27

176 171

Cl Cl

FORMULA 28 FORMULA 29 ^H 3 ^C ° 2 © ^

T 0-S0o-CF ₃ Cl

MODEL 30

C (Cń H5) ₃

MODEL 33

176 171

COOCHo ©

OH

MODEL 34

COOCHi c,

OH

MODEL 36L-OH

COOCH ₃

Y ^ CN o _v ch ₃

ABOUT

MODEL 35

COOCH3

T CN OSO ₂ CF ₃

MODEL 37

W! < ^{C (c} 6 ^h 5J3

MODEL 40

176 171

176 171

176 171

176 171

MODEL 58

176 171

176 171

176 171

Publishing Department of the UP RP. Circulation of 70 copies. Price PLN 6.00.

Claims (6)

Patent claims 1. Trisubstituted biphenyls of the general formula 1, wherein R ¹ is a carboxyl or CrCf, alkoxycarbonyl, R ² represents unbranched or branched C CrCo-alkyl, R ³ is fluorine chlorine and bromine, hydroxy, cyano, C1-C6 -alkoxy, branched or unbranched CrCo-alkyl, trifluoromethyl, trifluoromethoxy, carboxamido, carboxyl, C1-C6-alkoxycarbonyl or nitro and ^R4 represents tetrazolyl residue, and salts thereof. 2. Trisubstituted biphenyls of the general formula 1 according to claim 1 R 1 is a carboxy residue or a C 1 -C 4 alkoxycarbonyl residue, R ² is an unbranched or branched group, C 1 -C 8 alkyl, R 3 is fluoro, chloro, bromo, hydroxy, cyano, C 1 -C 3 alkoxy, unbranched or branched C1-C4-alkyl, trifluoromethyl, trifluoromethoxy, carboxamide, carboxyl, C1-C4-alkoxycarbonyl or nitro group, and R4 is a tetrazolyl residue, and salts thereof. 3. The trisubstituted biphenyls of general formula 1 according to claim 1 Is a carboxyl, methoxycarbonyl or ethoxycarbonyl group, R2 is propyl, butyl or pentyl, R3 is fluoro, chloro, hydroxy, cyano, methyl, methoxy, ethoxy, ethyl, trifluoromethyl, trifluoromethoxy, carboxy, carboxy, methoxycarbonyl, ethoxycarbonyl or nitro, and R4 is a tetrazolyl moiety, and salts thereof. 4. A trisubstituted biphenyl of the general formula 1 according to claim 1 1 which is 6-butyl-4-methoxycarbonyl-2-oxo-1 - [(3-fluoro-2'-tetrazol-5-yl-biphenyl-4-yl) -methyl] -1,2-dihydropyridine of formula 51. 5. Process for the preparation of trisubstituted biphenyls of formula 1, wherein R1 is a carboxyl residue or a C1-C6-alkoxycarbonyl residue, R2 is an unbranched or branched C1-C6-alkyl group, R3 is a fluorine, chlorine, bromine, hydroxyl, cyano group, C1-C6-alkoxy, unbranched or branched C1-C6-alkyl, trifluoromethyl, trifluoromethoxy, carboxamide, carboxyl, C1-C6-alkoxycarbonyl or nitro group, and R4 is a residue or tetrazolyl characterized in that (1) a pyridone of the general formula Is reacted in an inert solvent, in the presence of a base and optionally with the addition of a catalyst, with a compound of formula III in which r3 is as defined above, r4 is the residue of formula 8 and E is chlorine or bromine, the protective triphenylmethyl group is cleaved from the product obtained in a known manner, and the compound obtained is optionally salified. 6. The method according to p. 5. A process according to claim 5, characterized in that for the preparation of 6-butyl-4-methoxycarbonyl-2-oxo-1 - [(3-fluoro-2 ^, -tetrazol-5-yl-biphenyl-4-yl) -methyl] 1,2-dihydropyridine of formula 51, 6-butyl-4-methoxycarbonyl-2-oxo-1,2-dihydropyridine is reacted in an inert solvent in the presence of a base and optionally with the addition of a catalyst with 5- (4'-bromomethyl-3'-fluorobiphene) -2-yl) -N-triphenylmethyl-1H-tetrazole, the protective triphenylmethyl group is cleaved from the product obtained in a known manner. The invention relates to trisubstituted biphenyls and a process for their preparation. These compounds are used in medicaments, especially as blood pressure lowering agents and as anti-atherosclerotic agents. It is known that renin, which is a proteolytic enzyme, cleaves angiotensin I decapeptide in vivo from angiotensinogen, which again in the lungs, kidneys or other tissues is reduced to angiotensin Π octapeptide, causing an increase in blood pressure. The various effects induced by angiotensin II, such as, for example, vasoconstriction, retention of Na + ions in the kidney, release of aldosterone in the adrenal gland and increase in sympathetic nervous system tone synergistically increase blood pressure. In addition, angiotensin II contributes to the growth and multiplication of cells, such as, for example, heart muscle cells and smooth muscle cells, which causes these tissues to overgrow and proliferate during various disease states (e.g. hypertension, atherosclerosis, heart failure). . One of the possible interference with the renin-angiotensin system (RAS) is, in addition to inhibiting the activity of renin, inhibition of the activity of the angiotensin conversion enzyme (ACE) as well as blocking angiotensin II receptors. European Patent Applications Nos. EP 487 745 and 500 297 describe pyridone substituted biphenyls which bring down blood pressure.