1-(para-thienylbenzyl)-imidazoles as agonists of angiotensin-(1-7) receptors and pharmaceutical composition containing thereof

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new 1-(p-thienylbenzyl)-imidazoles of the formula (I): , wherein indicated residues represent the following values: R(1) means halogen atom, (C1-C4)-alkoxyl, (C1-C8)-alkoxyl wherein one carbon atom can be replaced with heteroatom oxygen atom (O); R(2) means CHO; R(3) means aryl; R(4) means hydrogen halogen atom; X means oxygen atom; Y means oxygen atom or -NH-; R(5) means (C1-C6)-alkyl; R(6) means (C1-C5)-alkyl in their any stereoisomeric forms and their mixtures taken in any ratios, and their physiologically acceptable salts. Compounds are strong agonists of angiotensin-(1-7) receptors and therefore they can be used as a drug for treatment and prophylaxis of arterial hypertension, heart hypertrophy, cardiac insufficiency, coronary diseases such as stenocardia, heart infarction, vascular restenosis after angioplasty, cardiomyopathy, endothelial dysfunction or endothelial injures, for example, as result of atherosclerosis processes, or in diabetes mellitus, and arterial and venous thrombosis also. Invention describes a pharmaceutical composition based on above said compounds and a method for their applying also.

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 19 ex

 

The invention relates to new 1-(p-cyaniventer)-imidazoles of the formula (I):

which are potent agonists of receptors of angiotensin-(1-7) and expense associated with the stimulation of these receptors in endothelial cells production and release of the vasorelaxant, antithrombotic, and cardiotoxin transport substances - cyclic 3′,5′-guanosine monophosphate (cGMP) and nitric monoxide (NO) are valuable drugs for the treatment and prevention of arterial hypertension, hypercardia, heart failure, coronary heart disease like angina, heart attack, vascular restenosis after angioplasty, cardiomyopathies, endothelial dysfunction or

accordingly, endothelial damage, for example, as a consequence of atherosclerotic processes or diabetes, as well as arterial and venous thrombosis.

In applications EP-A-512675 and WO-94/27597 described dienylbenzene the imidazoles as antagonists of receptors of angiotensin II and their use for the treatment of hypertension, heart failure, migraine, Alzheimer's disease and as an anti-depressive drugs. Moreover, dienylbenzene imidazopyridine known from application EP-A-513979 as receptor antagonists and is of giotensin-II and their use for the treatment of hypertension, heart failure, migraine and Alzheimer's disease, as well as from US 5444067 as agonists of angiotensin-II and their use for the treatment of hypotension and hypoaldosteronism. Further application EP-A-534706 known dienylbenzene hintline and pyridopyrimidines and applications EP-A-510812 known dienylbenzene triazoles as antagonists of angiotensin II-receptor.

Described in this application 1-(p-cyaniventer)-imidazoles of the formula (I) and their use as agonists of receptors of angiotensin-(1-7) in these applications were not documented and are not obvious.

Unexpectedly shown that 1-(p-cyaniventer)-imidazoles of the formula (I) have a characteristic effect on the receptors of angiotensin-(1-7) and mimic the biological activity of the effector hormone angiotensin-(1-7).

The object of the invention, therefore, are the compounds of formula (I):

in which the aforementioned residues have the following meaning:

R(1) means

1. halogen;

2. hydroxyl;

3. (C1-C4-alkoxyl;

4. (C1-C8-alkoxyl, with 1-6 carbon atoms are replaced by heteroatoms O, S or NH, preferably O;

5. (C1-C4-alkoxyl, substituted saturated simple cyclic ether, as tetrahydropyran or tetrahydrofuran;

6. O-(C1-C4)-Ala the Nile;

7. O-(C1-C4-alkylaryl and

8. alloctype, unsubstituted or substituted by a Deputy from a number of: halogen, (C1-C3)-alkyl, (C1-C3-alkoxy or trifluoromethyl;

R(2) means

1. SNO;

2. COOH and

3. COO-(C1-C4)-alkyl;

R(3) means

1. (C1-C4)-alkyl and

2. aryl;

R(4) means

1. hydrogen;

2. halogen and

3. (C1-C4)-alkyl;

X means

1. oxygen;

2. sulfur;

Y means

1. oxygen and

2. -NH-;

R(5) means

1. hydrogen;

2. (C1-C6)-alkyl and

3. (C1-C4-alkylaryl;

moreover, R(5) can mean hydrogen only when Y is specified in 2. value;

R(6) means

1. (C1-C5)-alkyl;

in all their stereoisomeric forms and mixtures in any ratio, and their physiologically acceptable salts; except for compounds of formula (I), in which both R(1) denotes halogen and R(2) is specified in 2. and 3. value.

The term "alkyl", unless otherwise specified, means a linear or branched saturated hydrocarbon residues. This also applies to manufactured his or her deputies, as alkoxyl or the remainder S(O)m-alkyl. Examples of alkyl residues are methyl, ethyl, n-propyl, isopropyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl. Examples of alkoxyl is the tsya a methoxy group, ethoxypropan, n-propoxylate, isopropoxide. Examples of alloctype are fenoxaprop or naftussya. Preferred is fenoxaprop.

Alkenyl means hydrocarbon residues with one or more double bonds, in which the double bond may be located in any positions. Examples of alkenyl are vinyl, propenyl and butenyl.

Halogen means fluorine, chlorine, bromine or iodine, preferably chlorine or fluorine.

Aryl means phenyl or naphthyl, preferably phenyl.

In the substituted aryl residues, the substituents can be in any positions in relation to each other.

Examples arylalkyl residues are phenylmethyl (benzyl), phenylethyl, phenylpropyl, phenylbutyl, naphthylmethyl, naphtalate, naftilamin, naphthylmethyl.

If the compounds of formula (I) contain one or more acidic groups or basic character, the object of the invention are the corresponding physiologically acceptable salts, in particular pharmaceutically applicable salt. Thus, the compounds of formula (I)containing a group of acid character, such as one or more COOH groups, can be applied, for example, in the form of alkali metal salts, preferably sodium salts or potassium, or alkaline earth salts of metals, for example salts of calcium or magnesium, or in the form and manievich salts, for example in the form of salts with ammonia or organic amines or amino acids. The compounds of formula (I)which contain one or more basic, i.e. protonium, groups can also be used in the form of their physiologically acceptable additive salts with inorganic or organic acids, for example, in the form of hydrochloride, phosphates, sulfates, methanesulfonates, acetates, lactates, maleates, fumarates, malatov, gluconate, etc. If the compounds of formula (I) contain in the molecule at the same time group of the acidic and basic character, along with these salt forms of the invention also includes internal salts, the so-called betaines. Salt can be obtained from compounds of formula (I) in the usual ways, for example by combination with an acid or a base in a solvent or dispersant or other salts by anion exchange.

Under physiologically acceptable salts of the compounds of formula (I), for example, also need to understand the organic and inorganic salts, which are described in Remington′s Pharmaceutical Sciences (17th edition, s (1985)). On the basis of physical and chemical stability and solubility for groups of acidic nature preferred, in particular, salts of sodium, potassium, calcium and ammonium; for groups main character is preferred, in particular, salts of hydrochloric acid, sulfuric is acid, phosphoric acids or carboxylic acids or sulfonic acids, such as acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid and p-toluensulfonate.

The present invention relates, further, to solvate of the compounds of formula (I), for example hydrates or adducts with alcohols, and also derivatives of the compounds of formula (I), as, for example, esters, and prodrugs and active metabolites.

Preferred compounds of formula (I)in which:

R(1) means

1. chlorine;

2. hydroxyl;

3. a methoxy group, ethoxypropan, propyloxy;

4. methoxyethoxy, methoxypropane;

5. alliancegroup and

6. fenoxaprop;

R(4) means

1. hydrogen and

2. chlorine;

R(5) means

1. hydrogen and

2. (C1-C4)-alkyl;

R(6) means n-propyl and 2-isobutyl;

and the remaining residues have the above-mentioned value,

in all their stereoisomeric forms and their mixtures, and their physiologically acceptable salts.

Further, preferred compounds of formula (I)in which:

R(1) denotes halogen, preferably chlorine; (C1-C4-alkoxy, preferably a methoxy group, ethoxypropan, propyloxy, particularly preferably a methoxy group; or (C1-C8-alkoxyl, with 1-6 carbon atoms are replaced by heteroatoms is, S or NH, preferably O, preferably methoxyethoxy or methoxypropane;

R(2) means SNO;

R(3) means aryl, preferably phenyl;

R(4) denotes halogen, preferably chlorine, or hydrogen;

R(5) means (C1-C6)-alkyl, preferably methyl, ethyl, propyl, butyl;

R(6) means (C1-C5)-alkyl, preferably ethyl, propyl or butyl;

X is oxygen;

Y represents oxygen or-NH-;

in all their stereoisomeric forms and their mixtures, and their physiologically acceptable salts.

Highly preferred compounds of formula (I), which are compounds of formula (II):

in which the residues R(1), R(4), R(5), R(6) and Y have the above significance, in all their stereoisomeric forms and their mixtures, and their physiologically acceptable salts.

Also preferred compounds of formula (I)in which R(1) means (C1-C4-alkoxy or (C1-C8-alkoxyl, with 1-6 carbon atoms are replaced by heteroatoms O, S or NH, preferably O, and the remaining residues have the above significance, in all their stereoisomeric forms and their mixtures, and their physiologically acceptable salts.

Especially preferred are also the compounds of formula (I)in which R(2) means the SNO and the remaining residues have the above significance, in any and the stereoisomeric forms and their mixtures, and their physiologically acceptable salts.

Further, preferred compounds of formula (I)in which X is Oh and the remaining residues have the above significance, in all their stereoisomeric forms and their mixtures, and their physiologically acceptable salts.

As particularly preferred compounds of formula (I) should be called:

4-chloro-5-formyl-2-phenyl-1[[4-[2 - (n-butyloxycarbonyl)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole;

5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonyl)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole;

5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-propylenecarbonate)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole;

5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(ethoxycarbonylmethylene)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole;

5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(methoxycarbonylamino)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole;

5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-buylamisilonline)-5-isobutyl-3-thienyl]phenyl]methyl]-imidazole;

5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(etilamingidrokhlorida)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole;

sodium salt of 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(etilamingidrokhlorida)-5-isobutyl-3-thienyl]phenyl]methyl]-imidazole;

L-lysine salt of 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(etilamingidrokhlorida)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole;

Tris(hydroxymethyl)aminobutanova salt of 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(etilamingidrokhlorida)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole;

5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(methylaminoacetaldehyde)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole;

5-formyl-4-methoxyethoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonyl)-5-isobutyl-3-thienyl]phenyl]methyl]-imidazole;

5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonyl)-5-isobutyl-3-thienyl]-2-chlorophenyl]methyl]imidazole;

5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(etilamingidrokhlorida)-5-isobutyl-3-thienyl]-2-chlorophenyl]methyl]imidazole;

4-chloro-5-formyl-2-phenyl-1-[[4-[2-(n-butyloxycarbonyl)-5-n-propyl-3-thienyl]phenyl]methyl]imidazole;

5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonyl)-5-n-propyl-3-thienyl]phenyl]methyl]imidazole;

5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(methoxycarbonylamino)-5-n-propyl-3-thienyl]phenyl]methyl]imidazole;

5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-buylamisilonline)-5-n-propyl-3-thienyl]phenyl]methyl]-imidazole or

5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(methylaminoacetaldehyde)-5-n-propyl-3-thienyl]phenyl]methyl]imidazole;

and their physiologically acceptable salts.

The invention also relates to methods of preparing compounds of formula (I), which are characterized by the following represents the different stages of reactions:

a) derivatives of 4-chloro-5-formylindole formula (III):

in which R(3) have the above significance and which are described, for example, in Chem. Pharm. Bull., 24, 960-969 (1976), is subjected to the interaction with p-bromobenzylamine formula (IV):

in which R(4) have the above significance, to compounds of the formula (V):

in which R(3) and R(4) have the above meaning,

moreover, the alkylation can be performed in the presence of organic or inorganic bases, such as triethylamine, To2CO3or Cs2CO3in an inert solvent, such as dimethylformamide. The compounds of formula (IV) are commercially available or can be obtained in itself known methods;

b) compounds of the formula (V) with thiophene-3-Baranovich acids of the formula (VI):

in which R(6) has the above meaning and receipt of which is known from application EP-A-512675, can be converted into 1-(p-thienyl)imidazoles of the formula (VII):

in which R(3), R(4) and R(6) have the above significance. This reaction cross combination type Suzuki reaction is preferably carried out using palladium acetate-(II) and triphenylphosphine or tetracationic-FOS is enallage as catalysts in the presence of a base, as, for example, cesium carbonate or potassium, for example, in a mixture solvent of ethanol and toluene, at temperatures up to the boiling point of the solvent; the corresponding reactions are described, for example, Synthetic Commun., 11, 513 (1981); J. Med. Chem., 38, 2357-2377 (1995) and Liebigs Ann., 1253-1257 (1995);

(C) compounds of formula (VII) by removal of the protective tert-butilkoi group can be converted into sulfonamides of the formula

in which R(3), R(4) and R(6) have the above significance. This removal is preferably carried out by treating compounds of formula (VII) with organic acids, such as concentrated triftoruxusnaya acid, in the presence of anisole;

d) the compounds of formula (VIII) by substitution of the chlorine atom in position 4 of the imidazole cycle can be converted into compounds of formula (IX):

in which R(3) and R(6) have the above significance and R(1) means specified in 2.-8. the remains. This substitution of the chlorine atom can be realized, for example, by treatment of compounds of formula (VIII) using an alcoholate, which are formed in situ due to the impact of basis as NaOH or NaH, used, in General, as solvents alcohols, such as methanol, ethanol or onomatology ether of ethylene glycol, at temperatures from 50°s up to the boiling point of the alcohols./p>

Alternatively, the compounds of formula (IX)in which R(1) means (C1-C4-alkoxyl, due to breakdown of a simple ester, preferably a simple methyl ester, of the formula (IX) by treatment with concentrated acids, as HI and Nug, or using Lewis acids as F3, l3, VVG3, ll3or aparatow, preferably using VVG3in an inert solvent, such as, for example, CH2CL2that can be translated into the corresponding phenols, which are then themselves known ways you can enter into interaction with the suitable way of substituted halides, such as (2-bromacil)methyl ether or benzylbromide, in the presence of a base in an inert solvent at temperatures up to the boiling point of the solvent.

The corresponding simple diphenyl ethers can be obtained by reacting phenols of the formula (IX) with baronowie acids, as, for example, phenylboronic acid or 4-methoxyphenylalanine acid, in the presence of catalysts based on copper, as, for example, si(SLA)2; corresponding reactions are described, for example, in Tetrahedron Lett., 39, 2937-2940 (1998);

e) from sulfonamides of formula (IX) due to the interaction with R(5)-substituted esters of Harborview acid you can get sulfonylurea formula (Ia):

in which R(1), R(2), R(3), R(4), R(6) have the above significance and R(5) is specified in 2. and 3. value. This transformation can be done in the presence of a base, such as pyridine, and the reaction accelerator acylation, as a 4-pyrrolidinone, at temperatures from room temperature up to 150°C, but preferably at room temperature;

f) from sulfonamides of formula (IX) by treatment with R(5)-substituted isocyanates, or isothioscyanates, you can get a sulfonylurea of the formula (Ib):

in which R(1), R(2), R(3), R(4), R(6) and X have the above meaning and R(5) is specified in 2. and 3. value. The transformation can be done using R(5)-substituted isocyanates and R(5)-substituted isothioscyanates in the presence of a base in an inert solvent at temperatures from room temperature up to 150°C.

As suitable bases, for example, hydroxides, hydrides, amides or alcoholate of an alkaline or alkaline earth metals, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium hydride, potassium hydride, calcium hydride, sodium amide, potassium amide, sodium methylate, sodium ethylate or tert-butyl potassium. As inert solvents suitable ethers, like tetrahydrofuran, dioxane, ethylene glycol-dimethyl ether or diglyme, ketones, such as acetone or butanone, NITRILES, such as acetone is home to the thrill, nitrocompounds, as nitromethane, esters as ethyl acetate, amides, as dimethylformamide or N-organic, triamide hexamethylphosphoric acid, sulfoxidov as dimethyl sulfoxide, and hydrocarbons as benzene, toluene or xylenes. Further, also suitable mixture of these solvents with each other.

Sulfonylureas of the formula (Ib) are also produced by the interaction of amines R(5)-NH2with sulfanilamidnymi derivatives, which are derived from sulfonamides of formula (IX), for example, by treatment with phosgene or a substitute for phosgene, as triphosgene.

Sulfonylureas of the formula (Ib), the alternative can also be obtained by reacting the sulfonamides of formula (IX) with 2,2,2-trichloroacetamide derivatives suitable amine R(5)-NH2in the presence of a base in an inert high-boiling solvent, such as dimethyl sulfoxide, or from the corresponding obtained by the interaction with ethyl ether of Harborview acid, sulfonylureas formula (Ia) by affecting the appropriate amine R(5)-NH2in an inert high-boiling solvent, such as toluene, at temperatures up to the boiling point of the respective solvent, as described, for example, in J. Med. Chem., 38, 2357-2377 (1995) and in Bioorg. Med. Chem., 5, 673-678 (1997).

N-unsubstituted sulfonylureas of the formula (Ib)in which R(5) means bodoro is, can be obtained by saponification of sulfonamidnami resulting from the interaction of the sulfonamides of formula (IX) with bromine cyan in the presence of K2CO3in acetonitrile, using sulfuric acid at temperatures from -10°0°C.

According to well-known methods known from the literature (for example, works as Houben-Weyl, Methods der Organischen Chemie, ed. Georg Thieme, Stuttgart; Organic Reactions, John Wiley and Sons, Inc., New York; and Larock, Comprehensive Organic Transformations, VCH, Weinheim), by oxidation of the aldehyde group in the compounds of formula (I) you can then obtain the corresponding carboxylic acids, or esters of carboxylic acids, of the formula (I).

The invention relates also to compounds of formula (X):

in which R denotes hydrogen or a suitable protective group, such as, for example, (C1-C6)-alkyl, preferably tert-butyl, and the remainder R(1), R(2), R(3), R(4), R(6) have the above significance, in all their stereoisomeric forms and their mixtures, and their physiologically acceptable salts.

The compounds of formula (X) represent valuable intermediate products for receipt of proposed according to the invention compounds of formula (I). Further, the compounds of formula (X) have high affinity for the receptor of angiotensin-(1-7) and, thus, can be used as a drug for the treatment and/or prevention is olivani, which are primarily or secondarily due to, or at least Sobolevsky, reduced production and/or release of the vasorelaxant, antithrombotic, and cardiotoxin transport substances - cyclic 3′,5′-guanosine monophosphate (cGMP) and nitric monoxide (NO)is, for example, for the treatment and/or prevention of hypertension, hypercardia, heart failure, coronary heart disease like angina, heart attack, vascular restenosis after angioplasty, cardiomyopathies, endothelial dysfunction or endothelial damage, for example, as a consequence of atherosclerotic processes or diabetes, as well as arterial and venous thrombosis.

The vascular endothelium is a metabolically active organ with many regulatory functions, which makes it able for the synthesis and release of vasoactive substances. Dysfunction is lined by vascular endothelial layer is correlated due to the pathogenesis of various cardiovascular diseases such as arteriosclerosis and hypertension (Eur. J. Clin. Invest., 23, 670-685 (1993)). Endothelial dysfunction is characterized by reduced synthesis and/or release of vasodilator, assamite, antithrombotics and antiproliferative active transport of substances - NO and cGMP-that is grout significant role in the prevention and regression of vascular reconstruction and hypertension. Substances that can stimulate the synthesis and release of these substances, therefore, are valuable drugs for the treatment of all diseases that are characterized by endothelial dysfunction.

Thanks to the many published experiments proved that the product of the cleavage system the renin-angiotensin, heptapeptide angiotensin-(1-7), a potent endogenous effector hormone system the renin-angiotensin (Hypertension, 18 [Appendix III], III-126 III-133 (1991)), the biological effect which is due to the stimulation of specific receptors that preferentially bind angiotensin-(1-7) (Peptides, 14, 679-684 (1993); Hypertension, 29 [part 2], 388-393 (1997)). This action is in many cases directed against the vasoconstrictor actions of the hormone angiotensin II, respectively, oppositely directed (Hypertension, 30 [part 2], 535-541 (1997); Regulatory Peptides, 78, 13-18 (1998)). In publications in Hypertension, 19 [Appendix II]: II-49-II-55 (1992), and Am. J. Cardiol., 82, 17-19 (1998) have shown that angiotensin-(1-7) stimulates the production and/or release of NO/cGMP and prostaglandin E2and I2that is not blocked by pre-treatment with antagonists AT1and al2-receptor. In a publication in Hypertension, 27 [part 2], 523-528 (1996) described endothelialization and relaxation in the stroke coronary arteries of dogs and pigs, and in a publication in J. Cardiovasc. Pharmacol., 30, 676-682 (1997) described endothelialization relaxation intact, pre-tied at the expense of KCl art rats by angiotensin-(1-7)that is not affected by antagonists AT1-receptor. In publications in Peptides, 14, 679-684 (1993) and in Am. J. Physiol., 269, H313-H319 (1995) demonstrates the effect of angiotensin-(1-7), reducing blood pressure, long-term intravenous infusion via osmotic minimalis spontaneously hypertensive rats, and angiotensin-(1-7) in the case of normotensive rats at the same dose had no effect on blood pressure. In addition to these research published in Hypertension, 31, 699-705 (1998) have shown that intravenous infusion of antibodies against the angiotensin-(1-7) increases mean arterial blood pressure in awake, spontaneously hypertensive rats that were pre-treated with lisinopril and losartan. In a publication in Am. J. Hypertension, 11, 137-146 (1998) have shown that in people with essential hypertension detected distinctly lower levels of plasma angiotensin-(1-7)than in normotensive people.

In a publication in Hypertension, 28, 104-108 (1996) proved antiproliferative action of angiotensin-(1-7) on vascular smooth muscle cells and in the publication in Hypertension, 33 [part II], 207-211 (1999) proved the inhibition of proliferation of smooth muscle cells after damage is possible vascular tissue.

Moreover, angiotensin-(1-7) in the case of "loaded" sodium chloride, shot of normotensive Wistar rats has also renal effects as increased nutrient and diuresis (Am. J. Physiol., 270, F141-F147 (1996)).

Described in this application, the compounds of formula (I) are potent ones agonists postulated receptors of angiotensin-(1-7), which are preferably localized in the vascular (including vascular endothelium), kidney, Central nervous system and heart. They therefore mimic the above, oppositely directed against the angiotensin-II biological activity of the peptide hormone angiotensin-(1-7), which reduces the production and/or release of cGMP and NO from the endothelium, while not being exposed, as in the case of this hormone, fast metabolic destruction. By stimulating the production and/or release of these vasodilator, antithrombotic and cardiotoxin transport of substances described receptor agonists of angiotensin-(1-7) of the formula (I) therefore represent a valuable drug for the treatment and/or prophylaxis of diseases which are primarily or secondarily due to, or at least Sobolevsky, reduced production and/or release of the vasorelaxant, antithrombotic, and cardiotoxin transport is s substances cyclic 3′,5′-guanosine monophosphate (cGMP) and nitric monoxide (NO)-and, thus, they can be used, for example, in the treatment and/or prevention of hypertension, hypercardia, heart failure, coronary heart disease like angina, heart attack, vascular restenosis after angioplasty, cardiomyopathies, endothelial dysfunction, and, accordingly, endothelial damage, for example, as a consequence of atherosclerotic processes or diabetes, as well as arterial and venous thrombosis.

Stimulation of endothelial receptors of angiotensin-(1-7) using agonists of formula (I) triggers the release of vasodilator and protection for organs physiologically active substances. This mechanism differs from ACE inhibition and blockade AT1-receptor due to the avoidance of or low level of angiotensin II in the tissue (in the case of ACE inhibitors)or are not currently estimated effects that are associated with elevated plasma levels of angiotensin II (in the case of antagonists AT1-receptor).

The compounds of formula (I) and their physiologically acceptable salts, thus, can be applied in the case of an animal, preferably a mammal, and especially a human, in the quality of medicines individually, in the form of smase is with each other or together with other biologically active substances, in particular in the form of pharmaceutical preparations. The object of the present invention is therefore the use of compounds of formula (I) and/or their physiologically acceptable salts for obtaining a medicinal product for treatment or prevention of the above diseases, as well as pharmaceutical preparations which contain an effective dose of at least one of the compounds of formula (I) and/or its physiologically acceptable salts as an active ingredient along with conventional, pharmaceutically acceptable carriers and/or excipients. The pharmaceutical compositions can be designed for enteral or parenteral use and typically contain 0.5 to 90 wt.% the compounds of formula (I) and/or its physiologically acceptable salts. Number of biologically active substances of the formula (I) and/or its physiologically acceptable salts in pharmaceutical preparations is, in General, from 0.2 to 500 mg, preferably 1-300 mg

Used according to the invention of drugs which contain compounds of the formula (I) and/or their physiologically acceptable salts, you can enter enterline, for example, orally or rectally, for example in the form of pills, tablets, coated tablets, pills, granules, hard and soft gelatine capsules, solutions, such as water, alcohol or oil rastv the market, juices, drops, syrups, emulsions or suspensions. The introduction can also be carried out parenterally, for example subcutaneously, intramuscularly or intravenously, in the form of solutions for injection or intravenous infusion. Further, take into consideration the forms of application are, for example, percutaneous or local introduction, for example, in the form of ointments, creams, pastes, lotions, gels, sprays, powders, foams, aerosols or solutions, or use as implants.

Used according to the invention, the pharmaceutical preparations can be obtained according to known standard methods of preparation of pharmaceutical preparations. For this purpose, one or more compounds of the formula (I) and/or their physiologically acceptable salts together with one or more solid or liquid galenovye carriers and/or additives or excipients and, if desired, in combination with other medicinal biologically active substances with therapeutic or prophylactic effect, for example with active against cardiovascular drugs, such as calcium antagonists, ACE inhibitors, antagonists AT1receptors NO donor, receptor antagonists endothelin, openers potassium channels, inibitor phosphodiesterase, diuretics or αand β-blockers lead to suitable for the reception of the form or, accordingly, dozirovocnaya form, which can then be used as a drug in human medicine or animal.

As carriers use organic or inorganic substances which are suitable for enteral (e.g. oral) or parenteral (e.g. intravenous) administration or local applications and do not react with biologically active substances of the formula (I), for example water, vegetable oils, alcohols like ethanol, isopropanol or benzyl alcohols, 1,2-propandiol, polyethylene glycols, glycerol triacetate, gelatin, carbohydrate as lactose or starch, magnesium stearate, talc, lanolin, vaseline, acetonitrile, dimethylformamide, dimethylacetamide. For oral or rectal suitable features such dosage forms as tablets, coated tablets, capsules, solutions, preferably oily or aqueous solutions, syrups, juices or drops, then, suspensions or emulsions. You can also use a mixture of two or more media, for example, a mixture of two or more solvents, in particular also mixtures of one or more organic solvents with water. As additives or auxiliary substances, the pharmaceutical preparations may contain, for example, stabilizers and/or wetting, emulsifying agents, salts, for example, to influence n the osmotic pressure, giving lubricity tablets ingredients, preservatives, colouring agents and flavouring substances and/or flavouring agents, buffer substances. If desirable, they can also contain one or more other biologically active substances, for example one or more vitamins. The compounds of formula (I) and/or their physiologically acceptable salts can also be liofilizirovanny and received lyophilizate can be applied, for example, for the preparation of drugs for injection. Especially for local applications also use liposomal composition.

Dosage introduce biologically active substances of the formula (I) and/or its physiologically acceptable salt in the case of proposed according to the invention of application depends on the individual case and as usual it should be adjusted for optimum performance in individual circumstances. So, it depends on the kind and intensity of treatable diseases, as well as gender, age, weight and individual needs curable person or animal, the intensity and duration of the used connections, do you treat acute or chronic disease or prevention is conducted, or enter whether along with the compounds of formula (I) other biologically active substances. In General, the scope of doses for the treatment of the above diseases in which the ne is from about 0.1 mg to about 100 mg per kg per day with the introduction of an adult weighing about 75 kg to achieve the desired action. Preferred is the area of doses from 1 to 20 mg / kg / day (respectively, mg / kg of body weight). The daily dose can be entered as a single dose or divided into several, for example one, two, three or four individual doses. If necessary, depending on individual behaviour, it may be necessary deviation towards higher or lower from the specified daily dose. The pharmaceutical preparations normally contain 0.2 to 500 mg, preferably 1-300 mg, biologically active substances of the formula (I) and/or its physiologically acceptable salts.

The invention relates also to the use of preferred ones of the compounds that cause the stimulation of receptors of angiotensin-(1-7), which are localized, for example, vascular (including vascular endothelium), kidney, Central nervous system and heart, as medicines, preferably for oral administration or for use as substances that stimulate the production and/or release of the vasorelaxant, antithrombotic, and cardiotoxin transport substances-cGMP and NO - and which can be used as medicines for the treatment and/or prophylaxis of diseases which are primarily or secondarily due, or at least Sobolevsky, reduced production and/or Visu is the release vasodilator, antithrombotic or cardiotoxin transport substances - cyclic 3′,5′-guanozinmonofosfata (cGMP) and nitric monoxide (NO)-, in particular for the treatment and prevention of arterial hypertension, hypercardia, heart failure, coronary heart disease like angina, heart attack, vascular restenosis after angioplasty, cardiomyopathies, endothelial dysfunction, respectively, endothelial damage, for example, as a consequence of atherosclerotic processes or diabetes, as well as arterial and venous thrombosis.

List of abbreviations:

abs. - absolute

cGMP - cyclic 3′,5′-guanosine monophosphate

CH2Cl2- dichloromethane

DCI - desorption-chemical ionization

DMF - N,N-dimethylformamide

IT is the acetate

ESI - ionization electron spray

FAB - fast atom bombardment

so pl. - melting point

us. - rich

NO - nitric monoxide

CT room temperature

THF - tetrahydrofuran

IR inhibitory concentration

EC - effective concentration

The invention is illustrated by the following examples without limiting the scope of the claims.

Examples:

Example 1

4-Chloro-5-formyl-2-phenyl-1-[[4-[2-(n-butyloxycarbonyl)-5-isobutyl-3-thienyl]phenyl]meth is l]imidazol

a) 4-Chloro-1-[(4-bromophenyl)methyl]-5-formyl-2-phenylimidazol

A solution of 8.0 g (32,0 mmol) 4-chloro-5-formyl-2-phenylimidazole (obtained according to Chem. Pharm. Bull., 24, 960-969 (1976)) and 5.3 g (32,0 mmol) To a2CO3in 200 ml of absolute dimethylformamide is stirred for 20 minutes at room temperature. Then add dropwise a solution of 9.6 g (32,0 mmol) 4-bromobenzyl-bromide in 200 ml of absolute dimethylformamide, and the reaction solution is stirred for 6 hours at room temperature. Concentrated in vacuo, the obtained residue is treated with ethyl acetate, washed with water, 10%solution of KHSO4, 10%solution of NaHCO3and a saturated solution of sodium chloride and dried over sodium sulfate. Chromatographic purification remaining after removal of the ethyl acetate residue on SiO2using a mixture of ethyl acetate/heptane 1:4) as solvent allocate 11.5g specified connection in the form of a solid beige color.

So pl.: 92-95°

Rf(SiO2, ethyl acetate/heptane 1:4)=0,24

Mass spectrometry (ESI): m/e=375/377 [M+H]+

b) 4-Chloro-5-formyl-2-phenyl-1-[[4-[2-(N-tertbutylphenyl)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole

A solution of 7.2 g (22,6 mmol) 5-isobutyl-2-[(N-tert-butyl)sulfonamide]-thiophene-3-Bronevoy acid (known from bid, medium, small is in EP-A-512675) in 125 ml of ethanol at room temperature is added dropwise to a solution of 8.5 g (to 22.6 mmol) of the compound, obtained according to example 1A), and 800 mg tetranitroaniline-(0) in 100 ml of toluene. Add 26 ml of 2 M solution of Cs2CO3and the resulting reaction solution is stirred for 5 hours while boiling under reflux. Concentrate to dryness and the remaining residue is treated with a mixture of ethyl acetate with water in the ratio 1:1. The organic phase is separated, washed with water, dried over sodium sulfate and concentrated. Chromatographic purification of the residue on SiO2using a mixture of ethyl acetate/heptane 1:4) as solvent to obtain 6.7 g of the compound (b) in a solid white color.

So pl.: 104-105°

Rf(SiO2, ethyl acetate/heptane 1:2)=0,26

Mass spectrometry (ESI): m/e=570 [M+H]+

C) 4-Chloro-5-formyl-2-phenyl-1-[[4-[2-sulfonamide-5-isobutyl-3-thienyl]phenyl]-methyl]imidazole

A solution of 3.3 grams (5,96 mmol) of the compound obtained according to example 1b), and 3.5 ml (5,96 mol) of anisole in 33 ml triperoxonane acid is stirred for 48 hours at room temperature. Concentrated in vacuo to dryness and the residue treated with ethyl acetate. An ethyl acetate solution is washed with water, dried over sodium sulfate and concentrated. After chromatographic purification of the residue on SiO2using a mixture of ethyl acetate/heptane 1:1 as RA is the maker of the gain of 1.52 g of compound (C) in the form of a slowly crystallizing solid.

So pl.: 118-120°

Rf(SiO2, ethyl acetate/heptane 1:1)=0,32

Mass spectrometry (ESI): m/e=515 [M+H]+

d) 4-Chloro-5-formyl-2-phenyl-1-[[4-[2-(n-butyloxycarbonyl)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole

In argon atmosphere, a solution of 100 mg (0,19 mmol) of the compound obtained according to example 1C), 1.7 ml of absolute pyridine are mixed successively with 3 mg (0.02 mmol) of 4-pyrrolidinedione and 252 μl (0,19 mmol) of butyl ether of Harborview acid. The reaction solution is stirred for 24 hours at room temperature. Then add 0.7 ml of methanol, concentrated to dryness and the residue is treated with ethyl acetate. An ethyl acetate solution is then washed with 10%citric acid solution, water and saturated sodium chloride solution, dried over sodium sulfate and concentrated. Chromatographic purification obtained after removal of solvent the residue on SiO2using a mixture of ethyl acetate/heptane 1:1 receive, finally, 85 mg of target compound of example 1 in the form of an amorphous solid.

Rf(SiO2, ethyl acetate/heptane 1:1)=0,15

Mass spectrometry (FAB): m/e=614 [M+H]+

Example 2

5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonyl)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole

a) 5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-sulfonamide-5-isobutyl-3-thienyl]phenyl]-methyl]imidazole

A solution of 850 mg (of 1.65 mmol) of the compound obtained according to example 1C), in 25 ml of methanol is mixed with 665 mg (16,53 mmol) NaOH and stirred for 20 hours while boiling under reflux. The reaction solution is concentrated and the residue is treated with a mixture of ethyl acetate with water in the ratio 1:1, the pH value of the solution is set to 6 by adding 1 N. hydrochloric acid and the organic phase is separated. The aqueous phase is extracted 2 times with ethyl acetate and the combined organic phases are dried over sodium sulfate. Chromatographic purification obtained after removal of solvent the residue on SiO2using a mixture of ethyl acetate/heptane 1:1 as the solvent to obtain 690 mg of the compound (a) in the form of a yellow amorphous foam.

Rf(SiO2, ethyl acetate/heptane 1:1)=0,23

Mass spectrometry (FAB): m/e=510 [M+H]+

b) 5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonyl)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole

Specified in the title compound is obtained by introducing into the interaction of the compound obtained according to example 2A), with the butyl ether of Harborview acid as indicated in example 1d) method. Of 106 mg (0.21 mmol) of the compound obtained according to the about example 2A), after chromatographic purification on SiO2using a mixture of ethyl acetate/heptane 1:1 as solvent receive 75 mg of target compound of example 2 in the form of an amorphous foam.

Rf(SiO2, ethyl acetate/heptane 1:1)=0,18

Mass spectrometry (ESI): m/e=610 [M+H]+

Example 3

5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-propylenecarbonate)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole

Specified target compound is obtained by introducing into the interaction of the compound obtained according to example 2A), with propyl ether Harborview acid as indicated in example 1d) method. From 60 mg (0.12 mmol) of the compound obtained according to example 2A), after chromatographic purification on SiO2using a mixture of ethyl acetate/heptane 1:1 to obtain 61 mg of the target compound as an amorphous foam.

Rf(SiO2, ethyl acetate/heptane 1:1)=0,13

Mass spectrometry (ESI): m/e=596 [M+H]+

Example 4

5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-ethoxycarbonylphenyl)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole

The target compound is obtained by introducing into the interaction of the compound obtained according to example 2A), with ethyl ether of Harborview acid specified in p is the iMER 1d) method. From 60 mg (0.12 mmol) of the compound obtained according to example 2A), after chromatographic purification on SiO2using a mixture of ethyl acetate/heptane 1:1 to obtain 55 mg of the target compound as an amorphous foam.

Rf(SiO2, ethyl acetate/heptane 1:1)=0,10

Mass spectrometry (ESI): m/e=582 [M+H]+

Example 5

5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(methoxycarbonylamino)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole

A solution of 80 mg (0.16 mmol) of the compound obtained according to example 2A), to 43.3 mg (0.32 mmol) To a2CO3and 8.3 mg dimethylaminopyridine in 6 ml of diethylene glycol-dimethyl ether is mixed with a 16.8 μl (0.16 mmol) dimethyldicarbonate and then stirred for 1.5 hours while boiling under reflux. The reaction solution is concentrated to dryness and the residue is treated with a solution of ethyl acetate and 10%aqueous solution KN2RHO4in the ratio of 1:1. The organic phase is separated, washed 2 times with 10%aqueous solution KN2RHO4, dried over sodium sulfate and concentrated. Chromatographic purification of the residue on SiO2using a mixture of ethyl acetate/heptane 2:1 to obtain 55 mg of the target compound as an amorphous foam.

Rf(SiO2, ethyl acetate/heptane 4:1)=0,23

Mass spectrome the rija (ESI): m/e=568 [M+H] +

Example 6

5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-buylamisilonline)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole

A solution of 60 mg (0.12 mmol) of the compound obtained according to example 2A), in 2 ml of absolute dimethylformamide mix series with 48 mg (0.35 mmol) To a2CO3and 13.2 μl (0.12 mmol) of n-utilizationof and then stirred for 3 hours at boiling under reflux. To the reaction solution after cooling, add 15 ml of 10%aqueous solution KN2RHO4and the resulting solution was repeatedly extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated. The resulting residue is mixed with a mixture of ethyl acetate with diisopropyl ether and the precipitated precipitate is filtered off under vacuum. Drying the precipitate in vacuo obtain 55 mg of the target compound.

So pl.: 131-133°

Rf(SiO2, ethyl acetate/heptane 4:1)=0,30

Mass spectrometry (FAB): m/e=609 [M+H]+

Example 7

5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(etilamingidrokhlorida)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole

The target compound is obtained by introducing into the interaction of the compound obtained according to example 2A), with utilitarianism specified in the example is 6) method. From 60 mg (0.12 mmol) of the compound obtained according to example 2A), obtain 46 mg of the target compound.

So pl.: 105-106°

Rf(SiO2, ethyl acetate/heptane 4:1)=0,30

Mass spectrometry (ESI): m/e=581 [M+H]+

Example 8

5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(methylaminoacetaldehyde)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole

A solution of 80 mg (0.16 mmol) of the compound obtained according to example 2A), in 1.5 ml of dimethyl sulfoxide is mixed with a 30.4 mg (0,17 mmol) N-methyl-2,2,2-trichloro-ndimethylacetamide and 19.1 mg (0.47 mmol) of powdered NaOH and stirred for 1 hour at a temperature of 80°C. the Reaction solution is cooled, mixed with ice and the pH value is set to 4 by adding 2 N. hydrochloric acid. Dropped when this precipitate is filtered under vacuum, washed with water, dried and purified by chromatography on SIO, SIS2using a mixture of ethyl acetate/heptane 2:1 as solvent. Obtain 62 mg of the target compound in a solid white color.

So pl.: 102-103°

Rf(SIO, SIS2, ethyl acetate/heptane 4:1)=0,14

Mass spectrometry (ESI): m/e=567 [M+H]+

Example 9

5-Formyl-4-methoxyethoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonyl)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole

a) 5-Formyl-4-methoxyethoxy-2-phenyl-1-[[4-[2-sulfonamide-5-isobutyl-3-GANIL]-phenyl]methyl]imidazole

A solution of 200 mg (0.38 mmol) of the compound obtained according to example 1C), 7.8 ml etilenpropilendienovogo ether in an atmosphere of argon mixed with 155 mg (with 3.89 mmol) of powdered NaOH and then stirred for 5 hours at a temperature of 80°C. Concentrated to dryness and the resulting residue is treated with saturated solution of NaHCO3and ethyl acetate. An ethyl acetate phase is separated and the aqueous solution is repeatedly extracted with ethyl acetate. The combined organic phases, dried over sodium sulfate and concentrated. Chromatographic purification of the remaining residue on SiO2using a mixture of ethyl acetate/heptane 1:1 to obtain 140 mg of the compound (a) in the form of solids slightly yellow in color.

So pl.: 91-92°

Rf(SiO2, ethyl acetate/heptane 1:1)=0,12

Mass spectrometry (FAB): m/e=554 [M+H]+

b) 5-Formyl-4-methoxyethoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonyl)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole

The target compound is obtained by introducing into the interaction of the compound obtained according to example 9a), with the butyl ether of Harborview acid as indicated in example 1d) method. From 70 mg (0.13 mmol) of the compound obtained according Primera), after chromatographic purification on SiO2using a mixture of ethyl acetate/heptane 1:1 as the solvent to obtain 78 mg of the target compound of example 9 in the form of an amorphous foam.

Rf(SiO2, ethyl acetate/heptane 1:1)=0,107

Mass spectrometry (ESI): m/e=654 [M+H]+

Example 10

5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonyl)-5-isobutyl-3-thienyl]-2-chlorophenyl]methyl]imidazole

a) 4-Chloro-1-[(4-bromo-2-chlorophenyl)methyl]-5-formyl-2-phenylimidazol

Compound (a) is obtained by introducing into the interaction of 4-chloro-5-formyl-2-phenylimidazole with 4-bromo-2-chlorobenzylamino specified in example 1A) method. From 2.0 g (9,68 mmol) 4-chloro-5-formyl-2-phenylimidazole obtain 2.6 g of the compound (a).

Rf(SiO2, ethyl acetate/heptane 1:2)=0,56

Mass spectrometry (DCI): m/e=409/411 [M+H]+

b) 4-Chloro-5-formyl-2-phenyl-1-[[4-[2-(N-tert-butylsulfonyl)-5-isobutyl-3-thienyl]-2-chlorophenyl]methyl]imidazole

The compound b) is obtained by introducing into the interaction of the compound obtained according to example 10A), and 5-isobutyl-2-[(N-tert-butyl)sulfonamide]thiophene-3-Bronevoy acid as indicated in example 1b) method. From 2.0 g (4,88 mmol) of the compound obtained according to example 10A), obtain 1.2 g of the compounds (b) in light of measles is newago oil.

Rf(SiO2, ethyl acetate/heptane 1:2)=0,47

Mass spectrometry (FAB): m/e=604 [M+H]+

c) 4-Chloro-5-formyl-2-phenyl-1-[[4-[2-sulfonamide-5-isobutyl-3-thienyl]-2-chlorophenyl]methyl]imidazole

Compound (C) is obtained from the compound obtained according to example 10b), as indicated in example 1C) method. From 1.2 g (1,99 mmol) of the compound obtained according to example 10b), receive 606 mg of the compounds (C) as a yellow foam.

Rf(SiO2, ethyl acetate/heptane 1:2)=0,32

Mass spectrometry (FAB): m/e=548 [M+H]+

d) 5-Formyl-2-methoxy-2-phenyl-1-[[4-[2-sulfonamide-5-isobutyl-3-thienyl]-2-chlorophenyl]methyl]imidazole

The compound d) is obtained from the compound obtained according to example 10C), as indicated in example 2A) method. Of 400 mg (0.73 mmol) of the compound obtained according to example 10C), obtain 280 mg of the compounds (d) as a yellow amorphous foam.

So pl.: 60° (softening)

Rf(SiO2, ethyl acetate/heptane 1:2)=0,20

Mass spectrometry (ESI): m/e=544 [M+H]+

e) 5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonyl)-5-isobutyl-3-thienyl]-2-chlorophenyl]-methyl]imidazole

Compound (e) obtained by introducing into the interaction of the compound obtained according to example 10d), with the butyl ether of Harborview acid specified in the example of the 1d) method. From 200 mg (from 0.37 mmol) of the compound obtained according to example 10d), obtain 167 mg of the compounds (e) in a solid beige color.

So pl.: 58° (softening)

Rf(SiO2, ethyl acetate/heptane 1:1)=0,45

Mass spectrometry (ESI): m/e=644 [M+H]+

Example 11

5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonyl)-5-isobutyl-3-thienyl]-2-chlorophenyl]methyl]imidazole

The target compound is obtained by introducing into the interaction of the compound obtained according to example 10d), with utilitarianism specified in example 7) method. Of 74 mg (0.14 mmol) of the compound obtained according to example 10d), after chromatographic purification on SiO2using a mixture of CH2Cl2/methanol in a ratio of 20:1 receive up to 35 mg of target compound in a solid white color.

So pl.: 83° (softening)

Rf(SiO2, ethyl acetate/heptane 1:1)=0,30

Mass spectrometry (ESI): m/e=614 [M+H]+

Example 12

4-Chloro-5-formyl-2-phenyl-1-[[4-[2-(n-butyloxycarbonyl)-5-n-propyl-3-thienyl]phenyl]methyl]imidazole

a) 4-Chloro-5-formyl-2-phenyl-1-[[4-[2-(N-tert-butylsulfonyl)-5-n-propyl-3-thienyl]phenyl]methyl]imidazole

Compound (a) is obtained by introducing in collaboration is their connection, obtained according to example 1A), 5-n-propyl-2-[(N-tert-butyl)-sulphonamido]thiophene-3-Bronevoy acid (known from application EP-A-512675) specified in example 1b) method. Of 4.8 g (of 13.1 mmol) of the compound obtained according to example 1A), after chromatographic purification on SiO2using a mixture of ethyl acetate/heptane 1:3) as solvent to obtain 2.9 g of the compounds (a) in a solid white color.

So pl.: 140°

Rf(SiO2, ethyl acetate/heptane 1:2)=0,30

Mass spectrometry (FAB): m/e=556 [M+H]+

b) 4-Chloro-5-formyl-2-phenyl-1-[[4-[2-sulfonamide-5-n-propyl-3-thienyl]-phenyl]methyl]imidazole

The compound b) is obtained from the compound obtained according to example 12A), as indicated in example 1C) method. Of the 1.9 g (of 3.56 mmol) of the compound obtained according to example 12A), after chromatographic purification on SiO2using a mixture of ethyl acetate/heptane 1:1 as the solvent to obtain 1.1 g of the compounds (b) in a solid white color.

So pl.: 93-95°

Rf(SiO2, ethyl acetate/heptane 1:2)=0,18

Mass spectrometry (ESI): m/e=500 [M+H]+

c) 4-Chloro-5-formyl-2-phenyl-1-[[4-[2-(n-butyloxycarbonyl)-5-n-propyl-3-thienyl]phenyl]methyl]imidazole

Compound (C) is obtained by introducing into the interaction is a journey of connection, obtained according to example 12b), with the butyl ether of Harborview acid as indicated in example 1d) method. From 100 mg (0.20 mmol) of the compound obtained according to example 12b), after chromatographic purification on SiO2using a mixture of ethyl acetate/heptane 1:3 as solvent receive 90 mg of the compounds (C).

Rf(SiO2, ethyl acetate/heptane 1:1)=0,14

Mass spectrometry (ESI): m/e=600 [M+H]+

Example 13

5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonyl)-5-n-propyl-3-thienyl]phenyl]methyl]imidazole

a) 5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-sulfonamide-5-n-propyl-3-thienyl]phenyl]-methyl]imidazole

Compound (a) obtained by conversion of the compound obtained according to example 12b), as indicated in example 2A) method. Of 850 mg (1.70 mmol) of the compound obtained according to example 12b), after chromatographic purification on SiO2using a mixture of ethyl acetate/heptane 1:2 get 460 mg of the compounds (a) in a solid white color.

So pl.: 85-86°

Rf(SiO2, ethyl acetate/heptane 1:1)=0,22

Mass spectrometry (ESI): m/e=496 [M+H]+

b) 5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonyl)-5-n-propyl-3-thienyl]phenyl]methyl]imidazole

The compound b) is obtained by introducing into the interaction of the compound obtained according to example 13A), with the butyl ether of Harborview acid as indicated in example 1d) method. From 60 mg (0.12 mmol) of the compound obtained according to example 13A), after chromatographic purification on SiO2using a mixture of ethyl acetate/heptane 1:1 as the solvent to obtain 52 mg of the compounds (b).

Rf(SiO2, ethyl acetate/heptane 1:1)=0,18

Mass spectrometry (ESI): m/e=596 [M+H]+

Example 14

5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(methoxycarbonylamino)-5-n-propyl-3-thienyl]phenyl]methyl]imidazole

The target compound is obtained by introducing into the interaction of the compound obtained according to example 13b), with dimethyldicarbonate specified in example 5) method. 75 mg (0.15 mmol) of the compound obtained according to example 13b), after chromatography on SiO2using a mixture of ethyl acetate/heptane 2:1 as the solvent to obtain 66 mg of the target compound as amorphous solid.

Rf(SiO2, ethyl acetate/heptane 4:1)=0,18

Mass spectrometry (ESI): m/e=554 [M+H]+

Example 15

5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-buylamisilonline)-5-n-propyl-3-thienyl]phenyl]methyl]imide is angry

The target compound is obtained by introducing into the interaction of the compound obtained according to example 13b), with n-utilitarianism specified in example 6) method. Of 59 mg (0.12 mmol) of the compound obtained according to example 13b), after chromatography on SiO2using a mixture of ethyl acetate/heptane 1:1 as the solvent to obtain 54 mg of the target compound as amorphous solid.

Rf(SiO2, ethyl acetate/heptane 4:1)=0,25

Mass spectrometry (ESI): m/e=595 [M+H]+

Example 16

5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(methylaminoacetaldehyde)-5-n-propyl-3-thienyl]phenyl]methyl]imidazole

The target compound is obtained by introducing into the interaction of the compound obtained according to example 13b), with N-methyl-2,2,2-trichloroacetamido specified in example 8) method. From 70 mg (0.14 mmol) of the compound obtained according to example 13b), after chromatography on SiO2using a mixture of ethyl acetate/heptane 2:1 as the solvent to obtain 55 mg of the target compound as amorphous solid.

Rf(SiO2, ethyl acetate/heptane 4:1)=0,15

Mass spectrometry (ESI): m/e=553 [M+H]+

Example 17

Sodium salt of 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(ethylamino is arylsulfonamides)-5-isobutyl-3-thienyl]phenyl]methyl]-imidazole

220 mg (0.38 mmol) of the Compound obtained according to example 7 are mixed with the 3.7 ml of freshly prepared 0.1 M solution of sodium methylate and the resulting solution was stirred for 1 hour at room temperature. The reaction solution is concentrated to dryness and the obtained residue slightly when heated, dissolved in 4 ml of n-butyl ester of acetic acid. Vykristalizovyvalsya after standing for three days in the refrigerator, the precipitate is filtered under vacuum and washed with a small amount of cold n-butyl ester of acetic acid. Drying under high vacuum gives, finally, 120 mg of the specified target sodium salt.

So pl.: 170°

Mass spectrometry (ESI): m/e=603 [M+H]+

Example 18

L-Lysine salt of 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(etilamingidrokhlorida)-5-isobutyl-3-thienyl]phenyl]-methyl]imidazole

A solution of 500 mg (0.86 mmol) of the compound obtained according to example 1, and for 125.8 mg (0.86 mmol) of L-lysine in 100 ml of ethanol and 25 ml of water is stirred for two hours at room temperature. Then concentrate to dryness, the residue is treated with 30 ml of water and the resulting solution is subjected to drying by freezing. The amorphous residue in an amount of 200 mg dissolved in 10 ml of hot toluene. After you remove the air traffic management in the refrigerator for several days vykristalizovyvalsya precipitate is filtered off and dried in high vacuum. Obtain 68 mg of the above compound as a pale yellow crystals.

So pl.: 180°

Mass spectrometry (ESI): m/e=727 [M+H]+

Example 19

Tris(hydroxymethyl)aminobutanova salt of 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(etilamingidrokhlorida)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole

A solution of 300 mg (0,516 mmol) of the compound obtained according to example 7, and 62.6 mg (0,516 mmol) of Tris(hydroxymethyl)aminomethane in 75 ml of ethanol and 15 ml of water is stirred for two hours at room temperature. Concentrate to dryness, the residue is treated with water and subjected to drying by freezing. The amorphous residue is dissolved in 30 ml of n-butyl ester of acetic acid. After keeping the solution in the refrigerator for several days vykristalizovyvalsya precipitate is filtered under vacuum and dried in high vacuum. Receive 120 mg of the target compound as a pale yellow crystals.

So pl.: 144-145°

Mass spectrometry (ESI): m/e=702 [M+H]+

In the following studies (test 1 and test 2) shows the affinity of the compounds of formula (I) to the binding sites of angiotensin-(1-7), as well as their agonistic properties in endothelial cells:

Test 1: Test against linking

Determination of the affinity of the compounds is of the formula (I) to the receptors of angiotensin-(1-7) was carried out by way of experiments on the displacement of the ligand in the membrane preparations of primary endothelial cells eort cattle, who, for example, also described in Hypertension, 29 [part 2], 388-393 (1997).

(a) Membrane preparation

After receiving the endothelial cell art cattle (test 1, a) cells were cultured until reaching their confluence in flasks for cultivation (Becton Dickinson, Heidelberg). After that, cells were treated with ice phosphate Nl-EDTU-buffer (50 mmol/l NaHPO4; 0.15 mol/l NaCl; 5 mmol/l EDTU; pH of 7.2), were separated using a rubber scraper and centrifuged (1500×g, 5 minutes). The precipitate cells after centrifugation was frozen (-80° (C) for the future of the membrane preparation. Thawed sediment cells homogenized in ice phosphate Nl-EDTU-buffer (vessels of glass with Teflon, 1000 rpm, 10 strokes). Selection of membranes was carried out by subsequent centrifugation (30000×g, 20 minutes) cell homogenate. The thus obtained precipitate cells after centrifugation resuspendable in modified HEPES-buffer (10 nmol/l HEPES; 0.1 mol/l NaCl; 5 mmol/l MgCl2; pH 7.4) with the addition of 0.2% bovine serum albumin and cocktail inhibitors-protease (Complete™, Boeringer Mannheim). After subsequent determination of protein (Lowry) in membrane suspensions her immediately used for experience in ligand binding.

b) Experiments in relation swazilan what I

The experiment was performed in 96-well tablets Opak are Durapore filters (pore size of 0.65 μm; Millipore, Eschborn). Before beginning experiences filters pre-treated with 1% bovine serum albumin for 30 minutes to minimize nonspecific binding of radioactive ligand and non-radioactive substances with the filter material. Incubation was carried out in a total volume of 200 μl: 50 μl125J-angiotensin-(1-7), 20 ml of non-radioactive angiotensin-(1-7) or the test compounds of the formula (I), 30 μl of buffer and 100 μl of membranes (20 μg protein). The binding reaction was initiated by adding radioactive ligand. Incubation of the samples was carried out with constant shaking at room temperature for 45 minutes. The binding reaction was finished by vacuum filtration (vacuum is 20 kPa; filtration system Multisreen, Millipore, Eschborn). To remove completely unrelated with the membrane free of radioactivity filters were washed in vacuum 2 times with 250 ál of ice phosphate Nl-EDTU-buffer (50 mmol/l NaHPO4; 0.15 mol/l NaCl; 5 mmol/l EDTU; pH of 7.2) and then dried. The radioactivity content in the dried filters was determined using the count of gamma radiation. For experiments on competition (the definition of "individual values or values IR50used the end is the acidity of 7.5-10 nmol/l 125J-angiotensin-(1-7) (specific activity 1500-2100 MCI/mg) with or without increasing concentrations of the test substances of formula (I). Nonspecific binding was defined, respectively, in the presence of 10 µmol/l non-radioactive angiotensin-(1-7).

(C) the Results

Example IR50[nmol]

2A 20

2b 30

4 5

7 20

The results confirm the high affinity of the compounds of formula (I) to the receptor of angiotensin-(1-7) in endothelial cells.

Against angiotensin II-receptor type AT1and al2the compounds of formula (I) have no affinity, respectively, show only the affinity, which can be neglected (>10-6M).

Test 2: the Study in terms of functionality

The definition of the stimulating action of the compounds of formula (I) on the production of intracellular cGMP as a marker for the production and release of NO in endothelial cells was carried out using primary cultured endothelial cells eort cattle, which, for example, described in J. Pharmacol. Exp. Ther., 262, 729-733 (1992).

a) Cell culture

After enzymatic cleavage (Dispase-II; Boeringer, Mannheim) endothelial cells of the aorta of cattle these endothelial cells were treated with culture medium (modified by the method Do ebecca eagle medium - Ham′s F 12 in the ratio of 1:1 with penicillin (10 Units/l), streptomycin (10 µg/l), L-glutamine and L-(+)-ascorbic acid (respectively, 5 mg/l) and inactivated by heat treatment of fetal calf serum (20%), washed 1 time (centrifugation at acceleration 170×g, 10 minutes) and resuspendable in culture medium. Produced sowing the thus obtained suspension of cells in 6-well plates (Nunc Intermed, Wiesbaden) (approximately 250 μg of protein or 3×10-5cells per well), supplemented with culture medium and kept at a temperature of 37°in hydrated and with an atmosphere of 95% O2and 5% CO2the incubator.

b) determination of cGMP

After reaching confluency (after 6-8 days after sowing) the culture medium was removed and the cell monolayer was washed 2 times with warm solution of HEPES/Tyrode. After that, the cells in a solution of HEPES/Tyrode, which contains IBMX (3-isobutyl-1-methylxanthines; 10-4mol/l; Serva, Heidelberg), pre-incubated for 15 minutes at a temperature of 37°C. the Incubation was initiated by adding SOD (superoxide dismutase erythrocytes of cattle, 3×10-7mol/l, Serva, Heidelberg) and the test substances of formula (I) in the indicated concentrations. After a suitable period of incubation, the incubation medium was aspirated, and the remaining the year immediately were extracted using a mixture of 1 N. formic acid-acetone (vol/vol, 15:85) and scraped. The resulting suspension was subjected to sonication (10 seconds) and then centrifuged (3000×g; 10 minutes). For determination of cGMP by using radioimmunoassay (New England Nuclear, Bosten, MA) supernatant liofilizirovanny and were processed using nitroacetate buffer (0.05 mol/l; pH of 6.2). Content (pmol) of intracellular cGMP was attributed to mg of cell protein.

(C) the Results

Example EC50[µmol]

2A 0,5

2b 0,3

4 0,1

7 0,5

The results confirm the agonistic activity of the compounds of formula (I) to the receptors of angiotensin-(1-7).

On the action proposed according to the invention compounds in relation to the production of cGMP as a marker for the synthesis and release of NO is not affected by pre-incubation with receptor antagonist of angiotensin II, a subtype al1as EHR and subtype al2as PD 123319. In contrast, described the stimulating effect of the proposed according to the invention compounds against cGMP inhibited by pre-incubation with selective receptor antagonist of angiotensin-(1-7), [D-l7]-angiotensin-(1-7), which is described, for example, Brain Res. Bull., 35, 293-298 (1994), which confirms the specificity of this functional effect.

The effect of the compounds of formula (I) at the heart of the show is but on the model of the isolated, functioning rat heart (test 3), which is described, for example, in J. Cardiovasc. Pharmacol., 8 [Appendix 10], 91-99 (1986).

Test 3: Isolated operating the hearts of rats

a) Method

Isolated hearts of rats Wistar-Kyoto (weighing 280-300 g) were perpendicularly method Langendorf using saturated with oxygen (95% O2with 5% CO2), not recirculating modified buffered solution of Krebs-Henseleit (118 mmol/l NaCl; 4.7 mmol/l KCl; 2.5 mmol/l CaCl2; 1.6 mmol/l MgSO4; 24,9 mmol/l Panso3; 1.2 mmol/l KN2RHO4; 5.5 mmol/l glucose, and 2.0 mmol/l sodium pyruvate) at a constant perfusion pressure of 60 mm Hg For measuring coronary flow served as placed in the pulmonary artery catheter with electromagnetic probes. After a period of equilibration of 15 minutes, the heart was transferred to the operating mode, which is set pre-load (end-diastolic pressure) 15 mm RT. Art. and additional load (load, overcome muscle while reducing) 60 mm Hg workload hearts remains constant during the whole testing time, accounting for more than 90 minutes. Related to the flow and pressure signals for the evaluation was recorded using the PLUGSYS measuring system (Hugo Sachs Elektronik). Data evaluation was performed using the determined the Oh every 2 seconds total frequency of 500 Hz when using software Aquire Plus VI.21f (PO-NE-MAH).

b) Results

When perfusion of the hearts (n=4) using a concentration of 10-6mol/l of the compound of example 2 in comparison with used as control hearts (n=4) identified the following values for coronary flow:

1. Processed heart:

Coronary flow [ml/min] Time [min]

8,92±0,68 0

11,29±0,90 5

12,17±0,74 10

12,22±0,10 15

2. Employees in the quality control of the heart:

Coronary flow [ml/min] Time [min]

8,98±0,59 0

8,94±0,52 5

9,04±0,70 10

8,91±0,44 15

Heart rate during the entire test in both groups remains unchanged.

This is a significant increase in coronary flow in isolated functioning hearts of rats confirms cardiotoxin action of the compounds of formula (I).

The effect of the compounds of formula (I) on collagen-induced platelet aggregation was investigated in the case of human platelet-rich plasma, which is described, for example, G.V.Born and others, Nature, 1962.

Test 4

a) Method

Human platelet-rich plasma (RPR) from 6 blood donors together with the test compound were incubated for 20 minutes at a temperature of 37°With, then activated by collagen and estimated maximum platelet aggregation in % light transmission.

b) the Result of

During incubation enriched platelet is mi plasma with 30 mmol of the compound from example 2 has determined the following values for the aggregation of trombocytes (n=6):

collagen (=maximum aggregation): 92±2,7 % aggregation

collagen +30 µmol connection example 2: 52±5,7% aggregation

This is a significant inhibition of platelet aggregation in human platelet-rich plasma confirms the antithrombotic activity of the compounds of formula (I).

1. 1-(p-Cyaniventer)-imidazoles of the formula (I)

in which the aforementioned residues have the following meaning:

R(1) means

halogen, (C1-C4-alkoxyl; and (C1-C8-alkoxyl, with 1 carbon atom may be replaced by a heteroatom About;

R(2) means SNO;

R(3) means aryl;

R(4) means hydrogen, halogen;

X is oxygen;

Y represents oxygen or-NH-;

R(5) means (C1-C6)-alkyl;

R(6) means (C1-C5)-alkyl;

in all their stereoisomeric forms and mixtures in any ratio, and their physiologically acceptable salts.

2. The compounds of formula (I) according to claim 1, in which:

R(1) denotes chlorine, methoxy group, ethoxypropan, propyloxy; methoxyethoxy, methoxypropane;

R(4) means hydrogen, chlorine;

R(5) means (C1-C4)-alkyl;

R(6) means n-propyl and 2-isobutyl;

and the remaining substituents have defined in claim 1 value

in all their stereoisomeric forms and their mixtures, and their physiologically acceptable salts.

3. The compounds of formula (I) according to any one of claims 1 and 2, which are compounds of formula (II)

in which the residues R(1), R(4), R(5), R(6) and Y are specified in claim 1 or 2 value

in all their stereoisomeric forms and their mixtures, and their physiologically acceptable salts.

4. The compounds of formula (I) according to any one of claims 1 to 3, characterized in that they represent:

4-chloro-5-formyl-2-phenyl-1[[4-[2-(n-butyloxycarbonyl)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole;

5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonyl)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole;

5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-propylenecarbonate)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole;

5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(ethoxycarbonylmethylene)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole;

5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(methoxycarbonylamino)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole;

5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-buylamisilonline)-5-isobutyl-3-thienyl]phenyl]methyl]-imidazole;

5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(etilamingidrokhlorida)-5-isobutyl-3-thienyl]phenyl]methyl] imidazole;

sodium salt of 5-form the Il-4-methoxy-2-phenyl-1-[[4-[2-(etilamingidrokhlorida)-5-isobutyl-3-thienyl]phenyl]methyl]-imidazole;

L-lysine salt of 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(etilamingidrokhlorida)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole;

Tris(hydroxymethyl)aminobutanova salt of 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(etilamingidrokhlorida)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole;

5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(methylaminoacetaldehyde)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole;

5-formyl-4-methoxyethoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonyl)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole;

5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonyl)-5-isobutyl-3-thienyl]-2-chlorophenyl]methyl]imidazole;

5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(etilamingidrokhlorida)-5-isobutyl-3-thienyl]-2-chlorophenyl]methyl]imidazole;

4-chloro-5-formyl-2-phenyl-1-[[4-[2-(n-butyloxycarbonyl)-5-n-propyl-3-thienyl]phenyl]methyl]imidazole;

5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonyl)-5-n-propyl-3-thienyl]phenyl]methyl]imidazole;

5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(methoxycarbonylamino)-5-n-propyl-3-thienyl]phenyl]methyl]imidazole;

5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-buylamisilonline)-5-n-propyl-3-thienyl]phenyl]methyl]imidazole; or

5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(methylaminoacetaldehyde)-5-n-propyl-3-thienyl]the dryer is l]methyl]imidazole;

and their physiologically acceptable salts.

5. The compounds of formula (X)

in which R means hydrogen or (C1-C6)-alkyl, and the remainder R(1), R(2), R(3), R(4), R(6) are specified in any one of claims 1 to 4 is, in all their stereoisomeric forms and their mixtures, and their physiologically acceptable salts.

6. The compounds of formula (I) according to any one of claims 1 to 4 as an agonist of receptors of angiotensin-(1-7).

7. The compounds of formula (X) according to claim 5 as an agonist of receptors of angiotensin-(1-7).

8. The pharmaceutical composition exhibiting the property of agonist receptors of angiotensin-(1-7), characterized in that it contains an effective amount of the compounds of formula (I) or (X) according to any one of claims 1 to 7 and/or its physiologically acceptable salt.

9. Agonists of the receptor of angiotensin-(1-7), which are compounds of formula (I) or (X), used for getting medicines for the treatment and/or prophylaxis of diseases which are primarily or secondarily due to, or at least Sobolevsky reduced production and/or release of the vasorelaxant, antithrombotic, and cardiotoxin transport substances - cyclic 3’,5’-guanosine monophosphate (cGMP) and nitric monoxide (NO).

10. Agonists of the receptor of angiotensin-(1-7), which are compounds of formula (I) and and (X), used for getting medicines for the treatment and/or prevention of hypertension, hypertrophy of the heart, angina, heart attack, vascular restenosis after angioplasty, cardiomyopathies, endothelial dysfunction, respectively, endothelial damage, for example, as a consequence of atherosclerotic processes or diabetes, as well as arterial and venous thrombosis.

Priority 05.05.1999, 19920815.8, DE items 1, 2, 3, 6, 4 compounds described in examples 1-16.

Priority 21.12.1999, 19961686.8, DE PP, 7-10, p.4 compound described in example 17.

Priority 29.04.2000 according to international application PCT/EP 00/03891 in claim 4 compounds described in examples 18 and 19.



 

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EFFECT: valuable medicinal properties of compounds and compositions.

16 cl, 1 tbl, 86 ex

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< / BR>
where R1benzyl, thienyl, chloranil, tetramethylene pentamethylbenzyl, phenyl, unsubstituted or monosubstituted by a halogen atom, a nitro-group, stands, metaxylem or trifluoromethyl, phenyl, disubstituted by chlorine atoms or methoxypropane,

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< / BR>
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2 ex

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16 cl, 2 dwg, 2 ex, 8 tbl

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1 ex

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1 ex

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