Imidazole derivatives or their physiologically compatible salts, method of production thereof, means for lowering high blood pressure and pharmaceutical composition for lowering blood pressure

 

(57) Abstract:

Essence: imidazole derivatives with the side chain of biganimalmovies or biphenylmethanol, method of their production and their use. The compounds of formula I

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where R1- e.g. ethyl, R2- e.g. methyl, N - e.g. O, R3- e.g. COOH and R4- e.g. SO2NHCONHCH3represent highly active antagonists of angiotensin II receptors. 4 C. and 3 h.p. f-crystals, 1 table.

The invention relates to imidazole derivative, method for their production and their use.

The development of a new angiotensin-11-receptor-antagonists attach increasing importance, taking into account the receipt of new active substances. From European patent A-28834 known, for example, 1-benzyl-substituted imidazole derivatives, from European patent A-253 310 known imidazole derivatives with function djarikatsebi acid and from European patent A-324 377 imidazole derivatives group diaryl-tetrazolyl and their use as antagonists of angiotensin 11 receptor.

In addition, in European patent A-0503162 presents 2-n-butyl-substituted imidazole derivatives having the structure biganimalmovies or biphenylamine describes the new derivatives of imidazole side chain of biganimalmovies or biphenylmethanol, which in position 2 imidazolate rings have a special Deputy R1and unexpectedly high angiotensin 11 receptor-antagonists in vitro and in vivo.

The invention relates to compounds of formula I:

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in which the symbols have the following meaning:

a) R1means (C4-C3)-alkyl, mainly n-propyl or ethyl, but especially n-propyl;

b) R2- 1. (C1-C6)-alkyl, mainly methyl,

2. (C3-C7-cycloalkyl,

3. phenyl or

4. benzyl;

c) R3- 1. hydrogen

2. CH2OR5,

3. CO-R6or

4. O-R7;

d) R4- 1. CO2NR7R8.

2. SO2-NR8-CO-NR7R9,

3. SO2-NH-COO-R7,

4. SO2-NH-SO2-NR7R9,

5. SO2-NH-CO-R7,

6. SO2-NH-SO2-R7or

7. SO2N = CH-N(CH3)2;

e) R5- 1. hydrogen or

2. (C1-C6)-alkyl;

f) R6- 1. hydrogen or

2. OR7;

g) R7, R9- same or different

1. hydrogen

2. (C1-C6)-alkyl, mainly methyl, ethyl or propyl,

3. (C3-C8
6. (C6-C10)-aryl-(C1-C4)-alkyl, preferably benzyl,

7. (C1-C9-heteroaryl, which may be partially or fully gidrirovanny,

8. (C1-C9-heteroaryl-(C1-C3)-alkyl, and the heteroaryl portion may be partially or fully gidrirovannah,

9. defined above in paragraphs 5, 6, 7 and 8 residue, substituted by 1 or 2 identical or different residues from the series halogen, hydroxy, (C1-C4)-alkyl, methoxy, nitro and cyano,

10. (C2-C6)-alkenyl or (C3-C6-alkanoyl,

11. (C3-C8)-cycloalkenyl,

12. (C3-C8)-cycloalkenyl-(C1-C3)-alkyl,

13. (C6-C10)-aryl-(C3-C6)-alkenyl,

14. (C1-C9-heteroaryl-(C3-C6)-alkenyl and

15. (C3-C6)-quinil;

h) R8denotes hydrogen;

i) n denotes 0, 1 or 2,

and their physiologically compatible salts.

Preferred compound of formula (I), in which

R1denotes ethyl or n-propyl, or their physiologically compatible salts. R1denotes especially n-propyl.

Preferred is also a compound of the formula I, in which R2The7, SO2NHCO-OTHER7or SO2-NH-CO-R7; R6denotes hydrogen or R7and R7denotes hydrogen or (C1-C6)-alkyl, as well as their physiologically compatible salts.

Alkyl, alkenyl and quinil can be straight or branched chain.

Under cycloalkyl include alkyl-substituted cycles.

(C6-C12)-aryl is, for example, phenyl, naphthyl or biphenyl, preferably phenyl.

Under (C1-C9) heteroaryl implies, in particular, residues, which are formed from phenyl or naphthyl, in which one or more CH groups are replaced by N and/or in which at least two adjacent CH groups (in the formation of five-membered aromatic ring) substituted by S, NH or O. Then one or both of the atom designated condensation of a bicyclic residues (as in indolizinyl) can also be N-atoms.

As heteroaryl act in particular furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazoles, hinely, ethanolic, phthalazine, honokalani, hintline, cinnolines.

Under physiologically tolerated salts of the compounds of formula I realize how their organic and inorganic salts, as they are described in Almington's Pharmaceutical Scinces (17th edition, page 1418 (1985)).

On the basis of physical and chemical stability and solubility of the acid groups are preferred, inter alia, salts of sodium, potassium salts, calcium salts, and ammonium salts; for major groups prefer, inter alia, salts of hydrochloric acid, sulfuric acid, phosphoric acid or of carboxylic acids or sulfonic acids, such as acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid and p-toluenesulfonic acid.

The invention relates also to method of obtaining new compounds of the formula I and their physiologically tolerable salts, which is characterized in that compounds of the formula II

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where

R1, R2, R3and n have the above definition, alkylate with compounds of formula III

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where

R4has the above definition and U denotes a volatile group, if necessary again otscheplaut temporarily introduced protective group transfer received sulfonamides of the formula I, if necessary, in the urethanes is obtained the compounds of formula I translated, if necessary, into their physiologically tolerated salts.

Suitable volatile groups U are predominantly nucleoprotein group (see Angew. Chem. 72 [1960] 71), as the halogen, o-toluensulfonate, mesilate or triplet.

Methods of obtaining the preliminary stages of formula I, are known inter alia from U.S. patent 4 355 044 and of the already mentioned European patent A-324 377 and A-323841.

Other ways to describe G. L affe (Chem. Rev. 69, 345 1969)), T. Srodsky ("The Chemistry of The Azido Groug, new York, 1971, page 331) H. Wamhoff ("Comprehensive Hetera cyclic Chemistry") and S. Katritzky (published by Pergamon Press, new York (1984)).

Another method of preparing compounds of formula II proceeds from derivatives of 2-oxime 1-cyanoglucosides acid and after the restoration of the oxime using known from literary reductants and attach merkaptosoedineny to the nitrile group with the use of suitable protective groups gives the preliminary stage, which in terms of removal of water can be collisional to imidazoles. For the cyclization stage can be applied between the way a mixture of PCl5and dimethylaminopyridine DMAP, POCl3and SOCl2and their mixtures with DMAP.

For the alkylation of compounds of formula II are used e.g. appropriate benzylchloride, benzalconium, benzylmethyl or sensitivity or the x compounds carried out in a known manner, for example, halogenoalkanes relevant metalowych preliminary stages. This is used primarily N-bromosuccinimide, see e.g. J. Org. Chem. 44, 4733 (1979) and Hel Chim. Acta 62, 2661 (1979).

Derivatives of biphenyl is possible to synthesize e.g. on the basis of the derived airborne acid by coupling with substituted aryl halides with catalysts of transition metals, especially palladium. Corresponding reactions describe R. B. Miller et al. al. (Organometallics 1984, 3, 1261) or A. Zuzuki et al. (Synthetic Commun. 11(7), 513 (1981)).

Derivatives sulfonylurea formula I can be obtained from the corresponding sulfonamides of formula I, the transformation esters harpalinae acids and bases, e.g. potassium carbonate, in an inert solvent, preferentially at temperatures up to the boiling point of the respective solvent.

Derivatives of sulfonylurea of the formula I can be obtained by choice or from the corresponding sulfonamides of formula I by transformation with isocyanates or derivative 2,2,2-trichloroacetamide appropriate amine in an inert, high-boiling solvents, e.g. DMSO (dimethyl sulfoxide) or from sulfonylureas formula I by reaction of the corresponding amine in an inert, high-boiling solvents, how to get sulfonyl-sulfonamides from the corresponding sulfonamides by transformation with anhydrides of sulfonic acids or sulfhemoglobinemia.

The remainder sulfonamida can, if required, be obtained from the amino group by rearrangement Meerwein. To do this, first diazotised amine hydrochloride and then turn it in the presence of a copper catalyst with sulfur dioxide in glacial acetic acid. Subsequent exposure to ammonia leads to sulfonamidnuyu group.

Sulfonamidnuyu group protects for example temporarily transfer to the group of 2N, N-dimethylbenzenesulfonamide. This translation is carried out at the same time, alternative or transformation of the corresponding sulfonamidnuyu compounds with N, N-dimethylformamidine or transformation of the corresponding sulfonamidnuyu compounds with N,N-dimethylformamide in the presence of a chip off the water funds, as SOCl3, POCl3, PCl3or complex ethyl esters of Harborview acid.

This protective group can be split as in the presence of a base and in the presence of acid.

Alternatively, you can appropriate thiophenol oxidation with chlorine and subsequent reaction with ammonia is converted into the sulfonamide.

The alkylation is carried out, in principle, by known methods in the same way.

The imidazoles of formula I is dy metals, as lithium hydride, sodium hydride or potassium hydride, for example, in dimethylformamide DMF) or dimethyl sulfoxide DMSO as solvents or metal alcoholate of the formula MOR, and R denotes a methyl, ethyl, tert.-butyl, and the reaction is carried out in the corresponding alcohol, dimethylformamide or dimethyl sulfoxide. Formed in this way salt derivatives of imidazole are dissolved in an aprotic solvent like dimethylformamide or dimethylsulfoxide and mixed with a suitable amount of alkylation agent.

An alternative possibility for deprotonation of imidazole derivatives is e.g. the transformation of potassium carbonate in dimethyl sulfoxide.

Oxidation of tizaidine formula (I) with n = 0 to the corresponding sulfones (n = 1) and sulfoxidov (n = 2) perform primarily above acids in appropriate solvents, such as, for example, CH2Cl2.

The interaction is carried out at temperatures below room temperature to the boiling point of the reaction mixture, mainly between +20oC and the boiling point of the reaction mixture for about 1 to 10 hours

The compounds of formula I according to the invention have an antagonistic action on Angie is e, they can be used in heart failure, cardiotoxic, myocardial infarction, hypertrophy of the heart, atherosclerosis, nephropathy, renal failure, and cardiovascular diseases of the brain, as transistor ischemic attacks and cerebral hemorrhage.

Renin is a proteolytic enzyme from the class of aspartyl-protease that is secreted as a result of various stimuli (volume reduction, lack of sodium, stimulation of receptors adjacent agglomerated cells of the kidney into the blood stream. There from isolated from liver angiotensinogen otscheplaut Decapeptide angiotensin I. His "enzymatic conversion of angiotensin" (ACE) is transferred to angiotensin II. Angiotensin II plays an essential role in the regulation of blood pressure, as it directly increases blood pressure as a result of angiospasm. Additionally, it stimulates the secretion of aldosterone from the adrenal gland and increases thus, through the inhibition of excretion of sodium in extracellular fluid volume, which contributes to high blood pressure.

Postreceptor actions are, among other things stimulation transformation phosphoinositol (Ca

The affinity of the compounds of formula I to angiotensin-II-receptor can be determined by measurement125J-angiotensin-II - or3H-angiotensin-II-displacement receptors on the membranes glomerulosa zones of the adrenal glands of cattle. For this purpose, the prepared membranes are suspended in a buffer solution at a pH of 7.4.

In order to prevent degradation of the radioactive ligand during incubation, add inhibitor of peptidases. Additionally use about 14.000 CPM of radioactive indicator with specific activity 74 TBg/mmol (sold by the firm Americhem buchler, Braunschweig, Germany) and the amount of the receptor protein, which binds 50% of the radioactive indicator. The reaction starts with the addition of 50 ml of membrane suspension in a mixture of 100 ml of buffer solution + Aprotinin; 50 ml buffer solution with angiotensin II with or without angiotensin-II or receptor antagonist and 50 ml of radioactive indicator. After the duration of the incubation period of 60 min at 25oC bound and free radioactive ligand is separated by sedimentation filtration (e.g. with WhatmanGFIC filters on Skadroncell collection).

Nonspecific prevent communication processing filters if p is to determine the displacement of the radioactive ligand to the receptor.

IC50- values, which indicate the concentration of the inhibitor to displace 50% of the ligand is determined by J. Theor. Biol. ol. 59, 253 (1970). They are for compounds of formula I in region 1 to 10-4- 1 - 10-9M

Alternatively, it is possible to determine the affinity of the compounds of formula I to angiotensin-II-receptor measurement 125H-angiotensin II or3H-angiotensin-II-displacement receptor preparitory from various organs (liver, lung, adrenal gland, brain, and so on).

For this purpose, the prepared membranes are suspended in incubation buffer solution (e.g. 20 mmol Tris, pH 7,4 containing 135 mmol NaCl, 10 mmol KCl, 10 mmol MgCl2, 5 mmol glucose, and 0.2% serum albumin cattle, and the protease inhibitors PMSF 0.3 mmol and bacitracin 0.1 mmol) and labeled with isotopic indicator of the angiotensin-II and various concentrations of the test compounds are incubated for 90 min at 25oC. Then bound and free radioactive ligand is separated by filtration through a filter from microtechnology (e.g. , GF51, Schleicher of Shull cell collection (SKYTRON).

The measurement of bound receptor radioactivity on the filters using beta or gamma range is essenia radioactive ligand to the receptor of the test compounds is defined as the IC50the concentration of inhibitor, which displaces 50% of bound radioactive ligand to the receptor. The calculation of the IC50- values produced with the assistance of software is proportional counter (e.g. LIGAND, G. A. Mc Pherson 1985, Elsevier - BIOSOFT, 68 Hills Road, Cambridge CB 2 ILA, U. K.). Measured for compounds of formula I IC50- values lie in the region 1 to 10-5- 1 10-11M

To determine the antagonistic action of the compounds of formula I in vivo can be measured for their inhibitory effect on induced by angiotensin II raises blood pressure on unlabeled radioactive isotope Spragul - Dawley-rats (Mellegard, Denmark). Intravenous use in the vein of the penis.

After preparation of the animal and a 20-minute time waiting for stabilizirovannye hemodynamic parameters appoint 3 consecutive injections of 10, 30 and 100 mg angiotensin II in 0.1 ml of an aqueous solution at intervals of 5 minutes the compounds of formula (I) dissolved in distilled water, under certain circumstances, with the addition of 10% ethanol and/or bases (pH < 10) or acid (pH > 3), at doses of 1 to 300 mg/kg administered intravenously or 5 - 1000 mg/kg intraduodenally.

When intraduodenally reaction to a medicinal substance increase blood pressure" occurs at intervals of 10 minutes

The compounds of formula (I) are particularly effective in the area of 1 to 300 mg/kg by intravenous appointment or 5 - 300 mg/kg during intraduodenal appointment.

The invention relates also to pharmaceutical dosage forms, consisting mainly of the compounds of formula I and, if necessary, from other active substances, e.g. diuretics or nesteroidnyi anti-inflammatory active substances. The compounds of formula I can also be used as diagnostic tools for system renin.

The pharmaceutical preparations contain an effective amount of the active substance of the formula I and, if necessary, other active substances together with organic or inorganic, used in pharmacy substance carrier and, if necessary, other additional or auxiliary substances. The application can be inside nasal, intravenous, subcutaneous, or through the mouth. The dosage of the active substance depends on the kind of a warm-blooded animal, body weight, age and the type of the destination.

The pharmaceutical preparations of the present invention receive famous is the link of active compound is mixed with the normal for this purpose additives, as a matter-carriers, stabilizers or inert solvents, and lead in suitable forms of administration, as tablets, pills, capsules, shell, aqueous, alcoholic or oily suspensions or aqueous, alcoholic or oily solutions. As inert carriers can be applied e.g. gum Arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose, fumarate magnesium or starch, especially corn starch. It is possible to obtain a formulation as a dry or moist granules. As oily substances carriers or solvents take into account, for example, vegetable or animal oils, like sunflower oil and fish oil.

For subcutaneous or intravenous administration, the active compounds or their physiologically tolerated salts, if necessary with conventional for this purpose substances as agents of dissolution, emulsifiers or other auxiliaries, they are solutions, suspensions or emulsions. As solvents take into account e.g. water, physiological sodium chloride solution or alcohols, like ethanol, propandiol or glycerol, as well as solutions of sugar, as glucose or mannitol, or a mixture of these dissolve the EE - the ethyl acetate

DCl - chemical ionization when Stripping

FAB - fast atom bombardment

RT - room temperature

mp - melting point

h - h (hours)

Min. - min (minutes)

The invention is explained in the following examples.

Example 1. Complex ethyl ester 1-[(2'-n-propylbenzenesulfonyl-biphenyl-4-yl)methyl] -2-n - propyl-4-methylthio-imidazole-5-carboxylic acid

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a) Complex ethyl ester 2-amino-2-cyano-acetic acid.

To 70 g (0,492 mol) of a compound ethyl ester 2-cyanoglucosides acid-2-oxime in 700 ml of water and 560 ml of a saturated solution of NaHCO3add at room temperature parts for 20 min 228 g (1,3 mol) of dithionite sodium. Stirred for 12 h at 35oC and after cooling and saturated NaCl, extracted with CH2Cl2. Drying with Na2SO4and concentration to dryness gives 30 g of the title compound as an oil, the ratio Rf(CH2Cl2/CH3OH 9/ = 0,6.

b) Complex ethyl ester of 2-cyano-2-n-profilerenumeration acid.

30 g (0,233 mol) of the compound from Ia) in 250 ml of absolute CH2Cl2and 18.9 ml (0,233 mol) of pyridine buried at 0 - 5oC solution and 24.2 ml (to 0.23 mol) of acid chloride of oil CT 3 H2O and 1 with a saturated solution of NaCl, dried with Na2SO4and concentrate. Crystallization from simple diisopropyl ether gives to 29.5 g of the title compound. Rf(CH Cl /MCO 9/1) = 0,7, melting point: 106oC.

c) Complex ethyl ester 3-amino-2-n-propylnitrosamine-3 - methylthiourea acid.

To 29,5 g (0,149 mol) of the compound from IB) and is 2.05 ml (0,0145 mol) of triethylamine in 500 ml of ethanol is added at room temperature 14.3 g (0,297 mol) of condensed mercaptan. After 4 days of incubation at room temperature the solvent is removed and the residue crystallized from simple diisopropyl ether, and get to 36.2 g of the title compound. Rf(CH2Cl2/minute 9:1) = 0,4.

Melting point: 119oC.

d) Complex ethyl ester of 2-n-propyl-4-methylthio-imidazole-5-carboxylic acid.

In 29,16 g (0,142 mol) pentachloride phosphorus in 240 ml of CH2Cl2buried at -78oC 19.3 g (of) 0.157 mol) of 4-dimethylaminopyridine in 120 ml of CH2CH2. After 10 minutes buried to 17.6 g (0,071 mol) of the compound from 1c) in 200 ml of CH2Cl2. Warmed to room temperature and stirred for 2.5 h at room temperature. Then, while cooling with ice add 1.6 l 1H. solution of NaHCO the United organic phases are dried with Na2SO4and concentrate. Chromatography on SiO2with CH2Cl2/EE 4/1 give 5.6 g of the title compound as oil.

Rf(CH2Cl2/EE 4:1) = 0,4, MS (DCl) : 229 (M + H).

e) Sulfonamides.

6 g (0,3 mol) of o bromoaniline in the atmosphere of argon added to a solution of 100 ml of concentrated HCl and 30 ml of glacial acetic acid at -10oC bury solution of 22.4 g of sodium nitrite in 30 ml of water and stirred the reaction solution 60 min at -5oC. the resulting solution was buried in rich SO2a solution of 7 g of CuCl22H2O and 0.5 g of CuCl in 300 ml of glacial acetic acid, the mixture after 60 min of stirring at room temperature, poured into a mixture of ice/water, extracted with simple ether, wash the ether extracts with saturated solution of NaHCO3and water, dried over MgSO4and concentrate. Received and 67.8 g sulphonylchloride compounds are mixed in 500 ml of acetone while cooling, 300 ml of concentrated ammonia. After removal of acetone, the resulting suspension is diluted with water, the precipitated white crystals are sucked off, washed with H2O and dried in high vacuum. The title compound without further purification used in the next reaction.

Melting point: 1 the EPA 1e) is stirred in 150 ml of absolute dimethylformamide with 40 ml of N,N-dimethylformamidine 2 h at room temperature. The reaction solution was poured on 200 ml of a 5% solution of NaHSO4/ice (1: 1), is sucked off settling sludge, washed with H2O and dried in vacuum. Get 67 g of the title compound.

Melting point: 148oC. Rf(SiO2), EE/heptane 1: 1) = 0,1, MS (DCl)6: 291/293 (M + H).

g) 4'-Methyl-biphenyl-2-N,N-dimethylbenzenesulfonamide.

To 11 g (of 37.9 mmol) of the compound from example 1f), 1 g of triphenyl phosphine, 8 g of Na2CO3in 150 ml of toluene and 40 ml of H2O add in an argon atmosphere at first 420 mg of Pd(OAc)2and then to 5.66 g (a 41.9 mmol) tolylboronic acid in 100 ml ethanol. Now heated 4 h to a boil, then concentrate and absorb in 500 ml of EE and 500 ml of H2O. the Resulting precipitate is filtered off them characterized as the title compound. EE-phase is separated, dried over Na2SO4and concentrate. Chromatography on SiO2with EE gives different part of the title compounds; total yield 7.6 g, melting point: 181 - 184oC, Rf (SiO2EE/heptane 1:1) = 0,2, MS (DCl): 303 (M + H).

h) 4'-Bromomethylbiphenyl-2-N,N-dimethylbenzenesulfonamide.

of 7.4 g (0,025 mol) of the compound from 1g) is heated with 4.6 g (0,026 mol) of N-bromosuccinimide in 130 ml of chlorobenzene in the presence of 300 mg of benzoyl peroxide 2 h before phlegmy. After cooling UB>2CO3, water and saturated NaCl solution, dried over Na2SO4and concentrate. The residue is stirred with EE and suck 6.7 g of the title compound.

Melting point: 168 - 171oC, Rf (SiO2, EE) = 0,5, MS (DCl) 381/383 (M + H).

i) Complex ethyl ester 1-[(2'-N,N-dimethylbenzenesulfonamide-biphenyl-4-yl)methyl]-2-n - propyl-4-methylthio-imidazole-5-carboxylic acid.

2.0 g (is 8.75 mmol) of the compound from 1d), 4.15 g (is 8.75 mmol) of the compound from 1h) (75%) and 1.25 g (9.0 mmol) of K2CO3) is stirred in 50 ml of absolute dimethylformamide overnight at room temperature. Concentrated, the residue is dissolved in 400 ml of EE, EE-solution is washed 3 with water, dried over Na2SO4and concentrate. The residue is stirred with ethanol and simple diisopropyl ether and sucked off to 4.14 g of the title compound precipitated as sludge.

Melting point: 169 - 171oC, Rf (SiO2, EE) = 0,4, MS (FAB): 529 (M + H).

j) Complex ethyl ester 1-[(2'-sulfonatophenyl-4-yl)methyl]- 2-n-propyl-4-methylthio-imidazole-5-carboxylic acid.

4 g (7,60 mmol) of the compound from 1i) is boiled in 40 ml of methanol with 20 ml of concentrated hydrochloric acid for 3 h with the phlegm. Cooled to room temperature, distilled dissolve the United EE-phase is dried over Na2SO4and concentrate. The resulting foam was stirred with ethanol and simple diisopropyl ether and the precipitate is sucked off. Get 3 g of the title compound.

Melting point: 125 - 127oC, Rf (SiO2, EE) = 0,7, MS (FAB): 474 (M + H).

k) Complex ethyl ester 1-[(2'-n-propylbenzenesulfonyl-biphenyl-4-yl)methyl]-2-n-propyl-4-methylthio-imidazole-5-carboxylic acid.

2 g (4,22 mmol) of the compound from 1j) in 50 ml of absolute acetone is mixed with 1.75 g (12,66 mmol) of anhydrous K2CO3. After 30 min of heating to phlegmy this solution is mixed with 395 l (4,22 mmol) propositionthe and stirred for 1 h with the phlegm. Then cooled, mixed with 15 ml of 2n. HCl, concentrated in vacuo and extracted several times with CH2Cl2. Drying over Na2SO4the concentration and crystallization of the EE network of 1.9 g of the title compound.

Melting point: 160 - 165oC, Rf (SiO2EE/heptane 2:1) = 0,25, MS (FAB): 559 (M + H).

Example 2. 1-[(2'-n-Propylbenzenesulfonyl-biphenyl-4 - yl)methyl]-2-n-propyl-4-methylthio-imidazole-5-carboxylic acid.

< / BR>
700 mg (1.25 mmol) of the compound from 1k) is stirred in 40 ml of methanol with 10 ml of 2n. NaOH solution for 3 days at room temperature. The solvent is then udalyat in high vacuum. Receive 600 mg of the title compound.

Melting point: 133 - 135oC, Rf (SiO2CH2Cl2/methanol 10/1) = 0,19, MS (FAB): 531 (M + H).

Example 3. Complex ethyl ester 1-[(2'-ethoxycarbonylmethylene-4-yl)methyl]-2-n-propyl-4-methylthio-imidazole-5-carboxylic acid.

< / BR>
1.5 g (3,17 mmol) of the compound from 1j) is boiled in an atmosphere of argon in 25 ml of absolute DME with 0,876 g (6,34 mmol) TO a2CO3and 0.35 ml (3,17 mmol) of a compound of the ethyl ether of Harborview acid 3 h with the phlegm. Then take away substantially solvent, establish the pH of the remaining solution using a 10% aqueous solution KH2PO4approximately 4 and extracted several times with EE. The United extracts are washed with saturated NaCl solution, dried over MgSO4concentrate and dry the residue under high vacuum. Get to 1.79 g of the title compound as a yellow foam.

Rf(SiO2, EE) = 0,5 MS (FAB): 546 (M + H).

Example 4. 1-[(2'-Ethoxycarbonylmethyl-biphenyl-4-yl)methyl]-2-propyl-4-methylthio-imidazole-5-carboxylic acid.

< / BR>
500 mg (to 0.92 mmol) of the compound from example 3) was stirred in 3 ml of ethanol with 2.5 ml of 2n. NaOH solution for 24 h at room temperature. The solvent is distilled in Wadowice sediment. Obtain 380 mg of the title compound in the form painted in faint yellow solid product.

Melting point: 156 - 160oC, Rf(SiO2), CH2Cl2/CH3OH 9/1/ - 0,3, MS (FAB): 518 (M + H).

Example 5. Complex ethyl ester 1-[(2'-methylaminoethylcarbonyl-biphenyl-4-yl)methyl]-2-ethyl-4-methylthiazole-5-carboxylic acid.

< / BR>
a) Complex ethyl ester of 2-cyano-2-ethylcarbodiimide acid.

The title compound receive specified in example 1B) method, and here instead of the acid chloride of butyric acid turn the acid chloride propionic acid with the compound of 1A). Out of 12.8 g (0.1 mol) of the compound of 1A) obtain 11.4 g of the title compound.

Melting point: 111 - 113oC, Rf(SiO2, EE) or = 0.6, MS (DCl) : 185 (M + H).

b) Complex ethyl ester 3-amino-2-ethylcarbodiimide-3-methyl-tigrillos acid.

This connection receive similarly indicated in example 1c) method.

Melting point: 127oC, Rf(SiO2, EE) = 0,18, MS (DCl): 233 (M + H).

c) Complex eyeloveu ester 2-ethyl-4-methylthio-imidazole-5-carboxylic acid.

This connection get like that shown in the 1d method.

The point has been melted down is sulphonamido-biphenyl-4-yl)-methyl]-2-ethyl-4-methylthio-imidazole-5-carboxylic acid.

The title compound is produced from compound 5c) and compounds 1h) described in example 1) method.

Melting point: 189 - 194oC, Rf(SIO, SIS2, EE) = 0,3, MS (FAB): 515 (M + H).

e) Complex ethyl ester 1-[(2'-sulfonatophenyl-4-yl)methyl]-2-ethyl-4-methylthio-imidazole-5-carboxylic acid.

The title compound prepared as in the method of example 1) from the compound of example 5d).

Melting point: 153 - 155oC, Rf(SiO2, EE), = 0,5 MS (FAB) : 460 (M + H).

f) 2,2,2-Trichloro-N-methyl-ndimethylacetamide.

1.6 g (51,5 mmol) of methylamine condense and mix in 20 ml of absolute dioxane with 7,14 ml (51,5 mmol) of triethylamine and 5.7 ml (51,5 mmol) trichloroacetamide dissolved in 10 ml of absolute dioxane, and the resulting solution stirred for 3 h at room temperature. Then mixed with water, set the pH value of the solution using a 2H. hydrochloric acid is approximately 1 and afterwards precipitated the title compound (7.6 g).

Melting point: 90 - 95oC.

(g) Complex ethyl ester 1-[(2'-methylaminoethylcarbonyl-biphenyl-4-yl)-methyl]-2-ethyl-4-methylthio-imidazole-5-carboxylic acid.

135 mg (0,316 mmol) of the compound from 5e) is stirred in 2 ml of absolute DMSO in atmospheres is 80oC. the Reaction solution was poured on ice water, acidified with 2n. hydrochloric acid and extracted several times with EE. After washing the United EE-phase saturated NaCl solution, drying over MgSO4and concentrating the resulting crystalline residue is stirred with a small amount of EE. Suction sludge gives 97 mg of the title compound.

Melting point: 220 - 223oC, Rf(SiO2CH2Cl2/CH3OH 9/1) OR = 0.6, MS (FAB): 517 (M + H).

Example 6. 1-[(2'-Methylaminoethylcarbonyl-biphenyl-4-yl)-methyl] -2-ethyl-4-methylthio-imidazole-5-carboxylic acid.

< / BR>
The title compound prepared as in the method of example 2 from the compound of 5g). From 50 mg (0.1 mmol) of compound 5g) receive 40.5 mg of the title compound.

Melting point: 155oC, Rf(SiO2CH2Cl2/CH3OH/ acetic acid 9/1/0,2) = 0,46, MS (FAB): 489 (M + H).

Example 7. Complex ethyl ester 1[(2'-ethoxycarbonylmethylene-4-yl)methyl]-2-ethyl-4-methyl-thio-imidazole-5-carboxylic acid.

< / BR>
1.4 g (3 mmol) of the compound from example 5e) and 825 mg (6 mmol) of K2CO3boiled in 25 ml of absolute dimethoxyethane boiled in 25 ml of absolute dimethoxyethane with 0.3 ml (3,05 mmol) of a compound ethyl aphiwat approximately pH 5 and extracted with EE. After drying over Na2SO4and concentrating obtain 1.45 g of the title compound.

Rf(SiO2), EE = 0,3, MS (FAB): 532 (M + H).

Example 8. Complex ethyl ester 1-[(2'-n-propylamino-carbonylmethyl-biphenyl-4-yl)methyl] -2-ethyl-4-methylthio-imidazole-5-carboxylic acid.

< / BR>
300 mg high (0.56 mmol) of the compound from example 7 is boiled in 7 ml of absolute toluene with 1.5 ml of n-Propylamine 3 h with the phlegm. After concentration and chromatography on SiO2and EE as solvent obtain 130 mg of the title compound.

Melting point: 202 - 203oC, Rf(SiO2), EE) = 0,24, MS (FAB): 545 (M + H).

Example 9. 1[(2'-n-Propylbenzenesulfonyl-biphenyl-4-yl)-methyl] -2-ethyl-4-methylthio-imidazole-5-carboxylic acid.

< / BR>
The title compound prepared as in the method of example 2 from the compound of example 8). From 100 mg (0.18 mmol) of compound 8) receive 70 mg of the title compound.

Melting point: 135 - 140oC, Rf(SiO2, EE) = 0,1, MS (FAB): 517 (M + M).

Example 10. Complex ethyl ester 1[(2'-n-propylbenzenesulfonyl-biphenyl-4-yl)methyl] -2-n-propyl-4-methylsulphonyl-imidazole-5-carboxylic acid.

< / BR>
95,0 mg (0,17 mmol) of the compound from example 1) are stirred in 10 with 10 ml of 10% aqueous solution of sodium bisulfite, warmed to room temperature and after separation of the phases are extracted with EE. The combined organic phases are washed with a saturated solution of Na2CO3, dried over Na2SO4and concentrate. Obtain 110 mg of the title compound.

Melting point: 65 - 68oC, Rf(SiO2, EE) = 0,1, MS (FAB): 575 (M + M).

Example 11. 1[(2'-n-Propylbenzenesulfonyl-biphenyl-4-yl)methyl] -2-n-propyl-4-methylsulfonyl-imidazole-5-carboxylic acid

< / BR>
The title compound is obtained from the compound of example 10) according to the method of example 2). From 100 mg (0,17 mmol) of the compound from example 10) obtain 83 mg of the title compound.

Melting point: 105 - 108oC, Rf(SiO2), EE) = 0,1, MS (FAB): 547 (M + M).

Example 12. Complex ethyl ester 1-[(2'-ethoxycarbonylmethyl-biphenyl-4-yl)methyl] -2-n-propyl-4-methylsulphonyl-imidazole-5-carboxylic acid.

< / BR>
350 mg (0.64 mmol) of the compound from example 3) is heated to 443 mg (1.28 mmol) of m-chlorbenzoyl acid (50%) in 20 ml of absolute CH2Cl21 h with the phlegm. Processing carried out similarly to the processing of example 10) and receive 364 mg of the title compound as a colorless foam.

Rf(SiO2), CH2Cl2(MCOH 9:1) = 0,74, MS (FAB): 578 (M + H).

OIC acid.

< / BR>
120 mg (0.2 mmol) of the compound from example 12) are obtained according to the method of example 2) and 84 mg of the title compound.

Melting point: 156 - 159oC, Rf(SiO2), CH2Cl2(MCOH 9:1:0,2) = 0,5 MS (FAB): 550 (M + H).

Example 14. Complex ethyl ester 1[(2'-ethylenediaminetetra-biphenyl-4-yl)methyl] -2-n-propyl-4-methylsulphonyl-imidazole-5-carboxylic acid.

< / BR>
The transformation of 200 mg (0.42 mmol) of the compound from example 1j) with 34 ml (0.42 mmol) utilizationof by way of example 1k) to give 170 mg of the title compound.

Melting point: 161 - 162oC, Rf(SiO2, EE) = 0,43, MS (FAB): 545 (M + H).

Example 15. 1-[(2'-Ethylenediaminetetra-biphenyl-4-yl)methyl]-2-n-propyl-4-methylsulphonyl-imidazole-5-carboxylic acid.

< / BR>
61 mg (0.11 mmol) of the compound from example 14) are obtained by the method of example 2) 56 mg of the title compound.

Melting point: 131oC, Rf(SiO2CH2Cl2, M2OH 10:1) = 0,2, MS (FAB): 517 (M + H).

Example 16. Complex ethyl ester 1-[(2'-allylaminogeldanamycin-biphenyl-4-yl)methyl]-2-n-propyl-4-methylthio-imidazole-5-carboxylic acid.

< / BR>
The transformation of 200 mg (0.42 mmol) of the compound from example 1j) with 38 ml (0.42 mmol) alkylsulfonate on spow): 557 (M + H).

Example 17. 1-[(2'-Allylaminogeldanamycin-biphenyl-4-yl)methyl] -2-n-propyl-4-methylthio-imidazole-5-carboxylic acid.

< / BR>
From 60 mg (0.1 mmol) of the compound from example 16) are obtained according to the method of example 2) 54 mg of the title compound.

Melting point: 148oC, Rf(SiO2CH2Cl2/MCOH 10:1) = 0.3, AND MS (FAB): 529 (M + H).

Example 18. Complex ethyl ester 1-[(2'-methoxycarbonylaminophenyl-biphenyl-4-yl)methyl]-2-n-propyl-4-methylthio-imidazole-5-carboxylic acid.

< / BR>
500 mg (1.06 mmol) of the compound from example 1j) is boiled with 293 mg (2,12 mmol) K2CO3, 106 ml (1.06 mmol) of dimethyldicarbonate and 53 mg DMAR in 20 ml simple dietilaminoetilovogo ether 2 h with the phlegm. Rotate, the residue is mixed with EE/solution KH2PO2, the organic phase is separated and after drying over Na2SO4concentrate.

Chromatography on SiO2(EE/heptane 2:1) to give 225 mg of the title compound.

Melting point: 146oC, Rf(SiO2, EE) = 0,37, MS (FAB): 532 (M + H).

Example 19. 1-[(2'-Methoxycarbonylaminophenyl-biphenyl-4-yl)methyl]-2-n-propyl-4-methylthio-imidazole-5-carboxylic acid.

< / BR>
Mixing 150 mg (to 0.263 mmol) of the compound from example 18) similarly, the connection UB>/MCOH 10:1) = 0,15, MS (FAB): 504 (M + H).

Example 20. Complex ethyl ester 1-[(2'-cyclopropanecarbonitrile-biphenyl-4-yl)methyl] -2-n-propyl-4-methylthio-imidazole-5-carboxylic acid

< / BR>
500 mg (1.06 mmol) of the compound from example 1j) is stirred with 408 mg (1.06 mmol) of dihydroxybenzenesulfonic (70%) and 85 ml (1.06 mmol) of pyridine in 20 ml of absolute CH2Cl22 h at room temperature. Then the reaction solution was again stirred for 2 h with 114 mg (1.06 mmol) cyclopropylmethyl-hydrochloride and 170 ml (2,12 mmol) of pyridine. Rotate, absorb the balance in EE, washed EE-phase solution of NaHCO3, solution of NaHSO4, dried over Na2SO4and concentrate. Chromatography on SiO2(EE/heptane 1:3) to give 72 mg of the title compound.

Melting point: 125oC, Rf(SiO2, EE) = 0,47, MS (FAB): 571 (M + H).

Example 21. 1-[(2'-Cyclopropanecarbonitrile-biphenyl-4-yl)methyl]-2-n-propyl-4-methylthio-imidazole-5-carboxylic acid.

< / BR>
Analogously to example 2) saponification 45 mg (0.08 mmol) of the compound from example 20) to give 34 mg of the title compound.

Melting point: 138oC, Rf(SiO2CH2Cl2/MCOH 9:1) = 0,1, MS (FAB): 543 (M + H)

Example 22. Complex ethyl ester 1-[(2'-pH">

< / BR>
Analogous to example 3) the transformation of 200 mg (0.42 mmol) of the compound from example 1j) with 70 ml (0,63 mmol) of complex propyl ether of Harborview acid gives, after chromatography on SiO2(EE/heptane 2:1) 200 mg of the title compound.

Melting point: 144oC, Rf(SiO2, EE) = 0,54, MS (FAB): 560 (M + H).

Example 23. 1-[(2'-propylacetophenone-biphenyl-4-yl)methyl] -2-n-propyl-4-methylthio-imidazole-5-carboxylic acid.

< / BR>
This compound is obtained from the compound of example 22) according to the method of example 2).

Melting point: 124oC, Rf(SiO2CH2Cl2/MCOH 10:1) = 0,1, MS (FAB): 532 (M + H).

Example 24. Complex ethyl ester 1-[(2'-benzyloxycarbonylamino-biphenyl-4-yl)methyl]-2-n-propyl-4-methylthio-imidazole-5-carboxylic acid.

< / BR>
Analogous to example 3) the transformation of 200 mg (0.42 mmol) of the compound from example 1j) with 89 ml (0,633 mmol) of a compound benzyl ether of Harborview acid gives, after chromatography on SiO2(EE/heptane 2:1) 250 mg of the title compound.

Melting point: 158oC, Rf(SiO2, EE) = 0,55, MS (FAB): 608 (M + H).

Example 25. 1-[(2'-Benzyloxycarbonylamino-biphenyl-4-yl)methyl] -2-n-propyl-4-methylthio-imidazole-5-carboxylic acid.

oC, Rf(SiO2CH2Cl2/MCOH 15:1) = 0,1, MS (FAB): 580 (M + H).

Data on the activity of specific compounds based on the values of IC50in examples 1 to 25. Moreover, the determination of the values of IC50was carried out on the basis of this text A - receptor relationships (see table).

1. Imidazole derivatives of General formula I

< / BR>
where R1- C1- C3-alkyl;

R2- C1- C6-alkyl, C3- C7-cycloalkyl;

R3is hydrogen, CH2OR5, COR6;

R4- SO2OTHER7, SO2NH-CO-NR7R9, SO2NHCOOR7, SO2NH-COR7;

R5is hydrogen, (C1- C6)-alkyl;

R6is hydrogen or or7;

R7and R9- same or different and denote hydrogen, C1- C3-alkyl, C3- C8-cycloalkyl,3- C8-cycloalkyl-C1- C3-alkyl, phenyl, phenyl-C1- C4-alkyl, C2- C6alkenyl;

n = 0, 1, or 2,

or their physiologically compatible salts.

2. Imidazole derivatives of General formula I on p. 1, where R1denotes ethyl or n-propyl, or their physiologically compatible salts.

3. Derived imidazo is 4. Imidazole derivatives of General formula I on PP.1 to 3, where R2- C1- C6-alkyl, R3- COR6n = 0, R4- SO2NH-COOR7, SO2NHCONHR7or SO2NHCOR7, R6is hydrogen or or7, R7is hydrogen or C1- C6-alkyl, or their physiologically compatible salts.

5. The method of obtaining the imidazole derivatives of General formula I

< / BR>
where R1, R2, R3, R4and n the specified values,

or their physiologically compatible salts, characterized in that the compound of formula II

< / BR>
where R1, R2, R3and n have the specified values,

subjected to interaction with the compound of General formula III

< / BR>
where R4has the specified values and U denotes tsepliaeva group and, if necessary, remove existing protection group transfer received sulfonamides of General formula I in the urethanes of the General formula I or translate the received sulfonamides of General formula I or the resulting urethanes of the General formula I in sulfonylureas of the General formula I with the separation of the target product in free form or in the form of a physiological compatible salt.

6. Medicine to lower high blood pressure, different thesize to lower blood pressure, containing the active principle and a pharmaceutically acceptable excipient, characterized in that the active principle is a compound of General formula I on PP.1 to 4 in an effective amount.

 

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