Substituted indonesianization, method for their preparation and use as pharmaceutical or diagnostic tools and medicines containing these compounds

 

(57) Abstract:

The present invention relates to substituted indonesianization formula I, where R1, R2, R3, R4, R5, R6represent hydrogen, alkyl, alkoxy, F, Cl, Br, I; R7, R8, R9, R10represent hydrogen, and X represents O. compounds of General formula I possess inhibitory activity against Na+/H+-exchange and can therefore be used as pharmaceuticals or diagnostic agents. The present invention relates also to a method for producing compounds of formula I by reacting the compounds of formula V where Y is alkoxygroup, halogen or imidazolium, with a guanidine of formula VI. 3 S. and 12 C.p. f-crystals, 2 PL.

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The present invention relates to indonesianization, method of production thereof, their use as pharmaceuticals or diagnostic drugs and medicines containing these compounds. Declare indonesianization have the formula I:

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where R1, R2, R3, R4, R5, R6separately or together represent predstavljaet a H;

X represents OH,

or are salts of the above compounds with non-toxic organic or mineral acid.

Examples of non-toxic pharmaceutically acceptable acids are hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonate acid, benzosulfimide, toluensulfonate, acetic acid, lactic acid, salicylic acid, benzoic acid, nicotinic acid, phthalic acid, stearic acid, oleic acid and oxalic acid.

The following terms in this description should be understood as follows:

"Alkyl" means a saturated aliphatic hydrocarbon which may be either straight or branched chain. Examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl, butyl, sec-butyl and tert-butyl.

The term "halogen" or "halogen" includes all four Halogens, namely fluorine, chlorine, bromine and iodine. In halogen-substituted groups having more than one substituent is halogen, the latter may be the same or different.

"Acyl" means an organic carbonyl radical lowest alanovoy acid. The most the P CLASS="ptx2">

"Aroyl" means the radical of an organic acid, such as benzoyl, toluyl.

"Lower alkanoyl" means an acyl radical of the lower alanovoy acid, such as acetyl, propionyl, butyryl, valeryl, stearyl and the like.

"Alkoxy" means alkoxygroup and includes hydroxyalkyl group. The most preferred alkoxygroup are methoxy, ethoxy, n-propoxy, isopropoxy, isobutoxy, n-butoxy, tributoxy.

The compounds claimed in the present invention include geometric isomers, and the invention applies to both E-and Z-isomers. The compounds claimed in the present invention may contain asymmetric centers, the invention relates to compounds as S and R configuration. The compounds can exist as optical isomers, racemates or mixtures thereof.

The invention also relates to a method for obtaining compounds of formula I, including the interaction of the compounds of formula

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where R1, R2, R3, R4, R5and R6have the meanings given above.

Y is a leaving group selected from O-C1-C4-alkyl, halogen or imidazolyl, with guanidine forms the s of the reaction product in the pharmaceutically tolerated salts.

Representatives of the compounds claimed in the present invention are listed in table. 1.

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where R5and R6- H, and X is oxygen; And - CH3SO3H.

Compounds of formula I are substituted acylhalides. The most famous representative of acylhalides is derived pyrazine amiloride, which is used in therapy as baltisberger of diuretic. The literature describes many other compounds like amiloride, such as, for example, dimethylaniline or ethylisopropylamine.

In addition, have been described antiarrhythmic properties of amiloride[(Circulation 79, 1257-1263(1989)]. However, its wide application as an antiarrhythmic agent is complicated by the fact that this effect is only slight and is accompanied hypotensive and securitycheck action, and these side effects are contraindicated in the treatment of cardiac arrhythmias.

Indications for antiarrhythmic properties of amiloride were also obtained in experiments with isolated animal heart [Eur. Heart J. 9 (supplement 1): 167 (1988) (book of abstracts)]. For example, for the hearts of rats, it was found that the artificially induced ventricular fibrillation can be the ID was even more potent, than amiloride.

Benzoylpyridine with antiarrhythmic properties described in European Offenlegungsschrift 416499.

U.S. patent 3780027 also describes acylhalides, which differ significantly from compounds with formula I, as claimed here described the invention, what they are tizamidine benzoylpyridine that the type of substitution are derived from those available on the market diuretics, as bumetanide and furosemide, and contain the amino group, which is important for search solidarities steps in position 2 or 3 in relation to the carbonyl group of guanidine. Accordingly reported strong solidarities activity of these compounds.

So was surprising that the compounds claimed in the invention, do not have harmful solidariteitsactie properties, but have a very good antiarrhythmic properties, therefore, they can be used for the treatment of disorders such as symptoms of oxygen deficiency. Thanks to its pharmaceutical properties of these compounds more other suitable as antiarrhythmic drugs, containing cardiotoxicity component for the prevention and logicheskie development of ischemic disorders, in particular the occurrence of ischemia provoked cardiac arrhythmias. Thanks to its protective effect against hypoxic and ischemic conditions of the claimed compounds of formula I can be applied due to inhibition of the cellular mechanism of exchange of Na+/H+as medicines for the treatment of all acute or chronic damage caused by ischemia or diseases, primary or secondary provoked by it. This applies to their use as medicaments for surgical intervention, such as organ transplantation, when these compounds can be used to protect the organs of the donor before and during removal, for the protection of removed organs, for example, when they are processed or stored in physiological fluids and transplantation in the recipient's organism. These compounds are also excellent medicines, which have a protective effect when performing plastic surgery on vessels, for example on the heart and peripheral vessels. In accordance with its protective effect against ischemic violations of these compounds are also suitable as drug peoplekey or swelling of the brain. Further, the claimed compounds of formula I are also suitable for the treatment of shock forms, such as anafilaktichesky, cardiogenic, hypovolemic and bacterial shock.

In addition, the claimed compounds of formula I are distinguished by the fact that exert a strong inhibitory effect on the proliferation of cells, such as proliferation of fibroblast cells and proliferation of cells of smooth and cardiac muscles. Thus, the compounds of formula I are potentially useful agents for the treatment of disease, primary or secondary cause of which is the proliferation of the cells, and therefore they can be used as antiatherosclerotic agents and agents that suppress long-term consequences of diabetes, cancer, fibrotic diseases, such as pneumovirus, fibrosis of the liver or kidney fibrosis, and hypertrophy and hyperplasia of the authorities, in particular prostate hyperplasia or hypertrophy of the prostate.

The claimed compounds are effective inhibitors of the cellular sodium/proton antiport (Na+/H+the antiporters), which in numerous diseases (essential hypertension, atherosclerosis, diabetes and the like), is also increased in such easily accessible to izobretenii compounds can be used as a beautiful and simple scientific tools, for example, when they are used in diagnostics for the detection and differentiation of forms of hypertension, but also of atherosclerosis, diabetes, proliferative diseases, and the like. In addition, the compounds of formula I apply to in the warning therapy to prevent the causes of high blood pressure, such as hypertension.

Additionally, it was found that compounds with the formula I have a favorable effect on serum lipoproteins. It is well known that extremely high content of lipids in the blood, so-called hyperlipemia is a significant risk factor in the development of arteriosclerotic changes of vessels, particularly coronary heart disease. For the prevention and regression of atherosclerotic changes decrease the increased level of serum lipoproteins is, therefore, extremely important. In addition to reducing the overall level of serum cholesterol reduction in the share of specific atherogenic lipid fractions that total cholesterol, particularly low density lipoprotein (LDL) and lipoprotein very low density lipoproteins (VLDL), is especially important, since these lipid fractions are atherogenic factor ricetta. Accordingly, hypolipidemic must be able not only to reduce total cholesterol, but also, in particular, LPN and LPN fraction of serum cholesterol. Now found that the compounds of formula I possess valuable therapeutically applicable properties in relation to impact on the level of serum lipids. So, they significantly reduce elevated concentrations of LDL and lonp, as to be expected, for example, resulting in increased intake of cholesterol from food and nutrition, enriched with lipids, or in the case of pathological changes of metabolism, such as genetic hyperlipemia. Thus, they can be used for the prevention and regression of atherosclerotic changes, by eliminating random risk factor. Such hyperlipemia include not only the primary hyperlipemia, but also some secondary hyperlipemia, such as occur in diabetes. Moreover, the compounds of formula I leads to a noticeable weakening of heart attacks caused by abnormalities of the metabolism and, in particular, to a considerable size reduction caused by a heart attack and its severity. In addition, the compounds of formula I provide effective protection against lesions caused metabolic the compounds of formula I are excellent drugs for the prevention and treatment of spasms of the coronary vessels, atherogenesis and atherosclerosis, of left ventricular hypertrophy and dilated cardiomyopathy, and thrombotic diseases.

These compounds therefore successfully used for various medicinal drugs used against hypercholesterolemia; for the prevention and treatment of atherogenesis; for the prevention and treatment of atherosclerosis, for the prevention and treatment of diseases caused by high cholesterol levels, for the prevention and treatment of diseases caused by endothelial dysfunction, for the prevention and treatment of hypertension caused by atherosclerosis, prevention and treatment of thrombosis, sprovotsirovannogo atherosclerosis, for the prevention and treatment of ischemic disorders and postischemic blood flow disorders caused by hypercholesterolemia and dysfunction of the epithelium, for the prevention and treatment of cardiac hypertrophy and cardiomyopathy caused by hypercholesterolemia and dysfunction of the epithelium, for the prevention and treatment of coronary artery spasm and myocardial infarction caused by hypercholesterolemia and dysfunction of the epithelium for the treatment of these conditions in combination with hypotensive substances, preferably with inhibitors of an enzyme is tipota (ABO) of the formula I with the compound, active in lowering blood lipids, preferably with an inhibitor of HMG-COA-reductase (i.e. lovastatin or pravastatin), where the latter has gipohloremicheskom action and thereby increases gipolipidemicheskie properties ABO inhibitor of formula I, is a profitable combination with high effect and less use of active compounds.

This invention also relates to a method for producing compounds of formula I. Obtaining the claimed compounds is illustrated by, but is not limited to the examples of the preparation of the representatives of the claimed compounds.

The synthesis of compounds with the formula I is carried out by means of an intermediate compound of formula III

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in which R1, R2, R3, R4, R5and R6defined above.

Connection with formula III getting known methods. One method is the cyclization of 3-phenylpropane acid with polyphosphoric acid.

The compounds of formula III are converted into acids with formula IV,

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where R1, R2, R3, R4, R5and R6same as above, by processing the Wittig reagent (Ph)3P+=CHCOOEt.Br-when tempatnya derivative with the formula V, where Y is alkoxygroup, preferably a methoxy group, an activated phenoxypropane, phenylthio, methylthio, 2-pyridylthio or nitrogenous heterocycle, such as imidazolyl, which can be obtained from the carboxylic acid (formula V, Y=Cl), which in turn can be obtained from the acid IV in the processing of chloride tiomila. Other activating ester techniques known in the chemistry of peptides, can be used to activate the acid in the reaction mixture. Imidazolidin with the formula V, Y= imidazolidin can also be obtained from compounds of formula IV by treatment with 1,1'- carbonyl diimidazol [C. Staab, Angew. Chem. Int. Eng Edn. 351-367 (1962)]. When processing a compound of formula VI under the reaction conditions, the Schotten's-Bauman compound of formula V (Y=Cl) also makes the connection with formula I. May be received by the other mixed anhydride of formula V, such as ClCOOEt, Teilhard, the acid chloride triethylphosphine acid, in the presence of triethylamine, or any other base in an inert solvent. Activation of the COOH group in the compounds of formula IV can also be achieved using DCC (dicyclohexylcarbodiimide). Other methods produce an activated carboxylic acid derivative type of formula V are given when the compounds of formulas V and VI can be carried out in a variety of ways in proton and aprotic polar solvents, however, the inert organic solvent is more preferable. In this context, methanol, THF, DMF, N-organic, hexamethylphosphoric-triamide, etc. in the range between room temperature and the boiling temperature of these solvents was convenient for the reaction of compounds V (Y= OMe) with guanidine. The reaction of compounds of formula V with guanidine in a free form with success runs in aprotic inert solvents such as THF, dimethoxyethane, DMF or dioxane. In case the connection with formula IV directly handle carbonyl diimidazol to activate the carboxyl group, use aprotic polar solvents, such as THF, dimethoxyethane, followed by addition of the compounds of formula VI. Connection with formula I can be converted into pharmacologically acceptable salt adducts of acids on the model of the salts indicated earlier in this description.

Active compounds claimed in the present invention, it is possible to assign orally, parenterally, intravenously, rectally or by inhalation, with the most preferred destination is a specific clinical need for this disease. In this regard, compounds with the formula I also can be applied in medicine. Specialist knowledgeable in this area, known from his special knowledge, any of the excipients are most suitable for the desired pharmaceutical preparation. In addition to the solvents can be used geleobrazovanie, suppositories, components, tablets and other active carriers compounds, antioxidants, dispersing agents, emulsifiers, anti-foam additives, fragrances, preservatives, soljubilizatory or dyes.

For the preparation of forms intended for oral administration, the active compounds are mixed with the appropriate this purpose additives, such as excipients, stabilizers or inert diluents, and brought to these suitable for the purpose of the form, as tablets, coated tablets, gelatin capsules, aqueous, alcoholic or oily solutions, by using conventional methods. Suitable inert components are, for example, gum Arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch. In this case, the preparation can be carried out both in the form of dry and wet granules. Acceptable oil mediums or solvents are, for example, vegetable or animal oils,active compounds required for these substances and traditional for this purpose soljubilizatorami, emulsifiers or other auxiliary preparations contribute to the solution, suspension or emulsion. Possible solvents are, for example, water, physiological saline solution or alcohols, e.g. ethanol, propanol, glycerol, as well as solutions of sugars such as glucose or mannitol or, alternatively, a mixture of these solvents.

Pharmaceutical compositions suitable for the purpose in the form of an aerosol or spray, represents, for example, solutions, suspensions or emulsions of the active compounds of formula I in a pharmaceutically acceptable solvent, such as, in particular, ethanol or water or a mixture of such solvents. If necessary, the composition may also contain other pharmaceutical excipients such as surfactants, emulsifiers and stabilizers, as well as gas-propellant. This product usually contains the active compound in a concentration of about 0.1 - 10%, in particular about 0.3 - 3% by weight.

The prescribed dose of the active compounds of formula I and the frequency of administration depends on the strength and duration of the used compounds and, optionally, also on the nature and severity of specific C is rednam daily dose of the compounds of formula I for a patient weighing 75 kg equal to at least 0.001 mg, preferably from 0.01 mg up to 10 mg, preferably a maximum of 1.0 mg In acute outbreaks, for example, immediately after the transfer of myocardial infarction may require even higher and, above all, more frequent doses, for example up to 4 individual doses per day. In particular for intravenous purpose, for example, a patient with an infarction in the intensive care unit, it may be necessary to 100 mg per day.

Experimental part

Synthesis of 4-methyl-1-indonesianationalclimatechangeact acid (compound No. 4 of the formula I in table. 1).

A. Synthesis of compound No. 4 of table. 1:

A. The synthesis of compounds with formula III:

3-(2-were)-propan-1-OIC acid (14 g, of 0.085 mol) is mixed with polyphosphoric acid (PFC, 140 g) and the mixture is heated at 80-85oWith mechanical stirring. After 1 hour the reaction mixture takes on a reddish color and the reaction is stopped by pouring the mixture into cold water. The obtained light-yellow precipitate is filtered off, washed with excess water, dried and purified by chromatography on a column for separation of the desired product, so pl. 91oC.

IR(KBr), cm-1: 2910, 1700, 1600, 1450, 1370, 1260, 1040, 790.


4-methylindene(4.5 g, 0.03 mol) is mixed with ethyltriphenylphosphonium (Wittig reagent, 10.4 g, 0.04 mol) in a round bottom flask, after which the mixture is heated for 5-6 hours in a salt bath at 190-200oC. the Reaction is stopped and the crude product is purified column chromatography. Chromatographically product then hydrolyzing a methanol solution of NaOH (2 equiv.) that gives 4-methyl-1-indanedione acid, so pl. 80oC.

IR(KBr), cm-1: 3100-2910, 1700, 1450, 1330, 1225, 950.

NMR(CDCl3), : is 2.40(s, 3H, CH3), 3,30(m, 2H, CH2), the 3.65 (m, 2H, CH2), of 6.50(s, 1H, = CH), 7,00-7,40(m, 3H, Ar-H).

C. Synthesis of compounds with formula 1:

4-methyl-1-indanedione acid (1.0 g, 0,0053 mol) is converted into the corresponding acid chloride (using the SO2Cl2). The acid chloride in THF (dry, 20 ml) was added dropwise to a suspension of guanidine base (0.9 g, 0.015 mol) in THF (dry, 20 ml) with stirring at room temperature. After addition, the reaction mixture is stirred for 1.2 hours and then the reaction stopped (after confirmation by TLC that the reaction is ended by addition of ice water (50 ml). The product is extracted with ethyl acetate (EA) (3 x 100 ml). An ethyl acetate layer is dried and considerationswhen acid is obtained by dissolving the free base in dry EA and adding 1.0 equivalent methanesulfonic acid. Salt is precipitated by cooling in a water bath, so pl. 225oC.

IR(Br), cm-1: 3350, 3150, 1710, 1620, 1490, 1380, 1170, 1050, 850.

NMR(DMSO-d3): 2,30 (s, 3H, CH3), is 2.40 (s, 3H, CH3SO3H) to 3.00(m, 2H, CH2), 3,30(m, 2H, CH2), 6,60(s, 1H, =N), 7,00-7,40 (m, 3H, Ar-H), 8.30 to (CA, 2H, NH2exchanged with D2O), 11,30 (CA, NH, exchanged with D2O).

Analysis%:

Calculated for C14H19N3O4S: C 51,69; H OF 5.84; N 12,92; S 9,84.

Found: 51,36; H 5,76; N 12,20; S 9,45.

Pharmacological methods for determining anti-arrhythmic and cardiotoxins steps:

Inhibition of sodium-proton exchange in erythrocytes of rabbit.

Rabbits, new Zealand albino line hold on 2% cholesterol diet for six weeks before taking a blood test for the determination of the activity of Na+/H+-antiporters in erythrocytes. It was reported that hypercholesterolemia increases the activity of antiporters in erythrocytes of rabbit (Scholts et al., Arteriosklerose - Neue Aspekte aus Zellbiologie und Molekulargenetik, Epidemiologie und Klinik, Assmann, G. et al., Eds., Braunschweig, Wiesbaden, Vieweg, 296-302). Samples of blood taken from the ear vein and determine hematocrite number. About 200 ml of blood thermostatic for 1 hour at 37oC in hyperosmotic sharethelove reaction stopped by adding 5 ml of ice-cold solution of MgCl2containing 0.1 mmol ouabain. The erythrocytes washed three times with a solution of MgCl2portions 5 ml. of Their hemolyzed by adding 4 ml of distilled water and determine the content of sodium in the hemolysate by flame photometry. Activity check connection is determined by its ability to reduce the content of sodium in the blood and expressed as an index IC50representing the concentration required to reduce the content of sodium in the blood by 50%.

1. Indonesianization formula I

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where R1, R2, R3, R4, R5, R6, separately or together represent H, C1-C4-alkyl, O-C1-C4-alkyl, F, C1, Br, I;

R7, R8, R9and R10represent H;

X represents OH,

or its pharmaceutically acceptable salt.

2. The compound of formula I on p. 1, suitable for the manufacture of a medicinal product for the treatment of heart arrhythmia.

3. The compound of formula I on p. 1, suitable for the manufacture of a medicine for treatment or prevention of myocardial infarction.

4. The compound of formula I on p. 1, suitable for the manufacture of the medicament is for the manufacture of a medicinal product for the treatment or prophylaxis of ischemic conditions of the heart.

6. The compound of formula I on p. 1, suitable for the manufacture of a medicinal product for the treatment or prophylaxis of ischemic conditions of the peripheral and Central nervous system and apoplexy.

7. The compound of formula I on p. 1, suitable for the manufacture of a medicinal product for the treatment or prophylaxis of ischemic conditions of peripheral organs and limbs.

8. The compound of formula I on p. 1, suitable for the manufacture of a medicine for treatment of shock.

9. The compound of formula I on p. 1, suitable for the manufacture of medicaments for use in surgical operations and organ transplants.

10. The compound of formula I on p. 1, suitable for the manufacture of medicaments for the preservation and storage of transplants for surgical procedures.

11. The compound of formula I on p. 1, suitable for the manufacture of a medicinal product for the treatment of diseases, primary or secondary cause of which is the proliferation of the cells, and, thus, its use as antiatherosclerotic means or agent against late complications of diabetes, cancerous diseases, fibrotic diseases, such as fibrosis of the Le is passed to the manufacture of scientific tools for inhibition of Na+/H+-antiporters and diagnosis of hypertension and proliferative diseases.

13. The compound of formula I on p. 1, suitable for the manufacture of a medicinal product for treatment or prevention of disorders of lipid metabolism.

14. The method of obtaining the compounds of formula I on p. 1, including the interaction of the compounds of formula V

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where R1, R2, R3, R4, R5and R6defined in paragraph 1, Y is a leaving group selected from-O-(C1-C4)-alkyl, halogen or imidazolyl, with a guanidine of formula VI

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where R7, R8, R9and R10defined in paragraph 1,

and, if desired, converting the reaction product in the pharmaceutically tolerated salts.

15. Drug, possess inhibitory activity against Na+/H+exchange containing the active compound and conventional additives, characterized in that active compound using an effective amount of the compounds of formula I on p. 1.

 

Same patents:

The invention relates to ortho-substituted-4-amino-benzoylpyridine formula (I):

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where

R1denotes A,

R2and R3each independently of one another, denote H, A, Ph or Het;

R2and R3together also denote alkylene with 4 or 5 C-atoms;

Het denotes a saturated, unsaturated or aromatic heterocycle with 1 or 2 nitrogen atoms or sulphur, linked via N or C, which is unsubstituted or once, twice or three times may be replaced with A

A denotes alkyl with 1-6 C-atoms;

Gal denotes F, Cl, Br or I; and

Ph denotes unsubstituted or once, twice or three times substituted with A, OA, NH2, F, Cl, Br and/or CF3,

and their physiologically acceptable salts

The invention relates to benzoylpyridine formula I

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where one of the three substituents R(1), R(2), and R(3) means-OR(10),

R(10) implies CaH2a-(C1-C9-heteroaryl-N-oxide, which is not substituted or is substituted by 1-3 substituents selected from the group consisting of CF3CH3,

a = 0, 1, 2;

accordingly, the other substituents R(1), R(2) and R(3) independently of one another mean

hydrogen, (CH2)p-(CqF2q+1), R(22) -SOuand performanceline group is a straight or branched chain

The invention relates to benzoylpyridine General formula (I)

(I)

where R(1) means hydrogen or R(5) - SOm,

m means 0, 1 or 2,

R(5) means (C1-C8)-alkyl,

R(2) means-CF2R(14), -CF[R(15)][R(16)],

R(14) means (C1-C4)-alkyl,

R(3) is defined as R(1),

R(4) means hydrogen, -(CH2)s-(CF2)t-CF3,

s denotes 0 or 1, t is 0, 1 or 2,

and their pharmaceutically compatible salts

The invention relates to novel ortho-substituted arylbenzothiazoles formula (I), where R1denotes A, CF3, Gal; R2and R3each independently of one another denote H, Gal A, SOn-R6, -SO2NR4R5, Ph; R4denotes H, A, CF3, Ph; R5denotes H or A; R6means; And means alkyl with 1-6 C-atoms; Ph denotes unsubstituted or one-, two - or three-fold substituted with A, F, Cl, Br, J or CF3phenyl; n is 1 or 2; Gal denotes fluorine, chlorine, bromine or iodine, and their physiologically acceptable salts, which have a good cardiostim action and is therefore particularly suitable for the treatment of myocardial infarction, prophylaxis heart attack and to treat angina

The invention relates to pharmaceutical compositions containing as active ingredient at least one substance inhibiting NO-synthetase, and at least one substance that traps the reactive forms of oxygen, and, optionally, a pharmaceutically acceptable carrier

The invention relates to a method for producing compounds of formula (I) consists in the fact that the compound of formula (IX):

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in which R1' has the abovementioned meaning and M represents a hydrogen atom or the radical R2' which has the values specified above for R2in which the possible reactive functions can be protected by a protective group, is subjected to reaction with the compound of the formula (VIII) defined above, to obtain a product of formula (X):

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in which R1' M and R4' have the above values, the obtained compound of formula (X), if M implies R2' defined above, is subjected to a halogenation reaction, to obtain the product of formula (XI):

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in which R1', R2', R4' and Hal have the above values, which is subjected to the reaction of the exchange of the halogen-metal, then the reaction with the compound of the formula (XII):

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in which R9' matter referred to in paragraph 1 for R9where possible reaction ф�g/rupat4/200110/01/2174513-36t.gif" ALIGN="ABSMIDDLE">< / BR>
in which R1', R2', R4' and R9' have the above meanings and, if necessary, or interact product of formula (I2) with the compound of the formula (XV):

O=C=N-R6' (XV)

in which R6' matter referred to in paragraph 1 for R6in which the possible reactive functions can be protected by a protective group, to obtain a product of formula (I3):

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in which R1', R2', R4', R6' and R9' have the above meanings, or the product of formula (I2) is subjected to a saponification reaction with the product of formula (I4):

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in which R1', R2', R4' and R9' have the above meanings, is subjected to reaction with COCl2to obtain a product of formula (I5):

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in which R1', R2', R4' and R9' have the above meanings, or the product of formula (X), provided that M denotes a hydrogen atom, is subjected to a halogenation reaction to obtain a product of formula (XIV):

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in which R1', R4'Hal and R3" have the above values, the compound obtained is subjected to the reaction of the exchange of the halogen-metal, then the processing of the compound of formula (IVa') (IVb'), (IVc'), (IVd') or (IVe') defined above, to obtain a product of formula (I7):

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in which R1', R4', R2and R3" have the above meanings; then the above products of formula I2, I3, I4, I5, I6, I7that are a product of the formula I, allocate or subjected, if necessary, one or more reactions of transformation to other products of the formula I, in any order:

a) esterification of the acid function,

(b) saponification functions of ester to acid functions,

C) transforming functions of ester function acyl,

d) transforming Sinopoli in an acid function,

e) conversion of the acid function to an alcohol function,

g) transforming functions alkoxy function hydroxyl or hydroxyl function in the function alkoxy,

h) oxidation of the alcohol function to the aldehyde, acid or keto-function

i) the conversion of the formyl radical in the radical carbarnoyl,

j) turning radical carbarnoyl in the nitrile radical,

k) converting the nitrile radical in tetrazolyl,

l) oxidation of ancilliary or aristocraty to the corresponding sulfoxide or sulfone,

m) the transformation function sulfide, sulfoxide or sulfone function corresponding sulfoximine,

n) the transformation function oxo function of thioxo,

a) transforming radical

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in radical

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p) conversion of the acid function in function

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q) is the transformation function of beta-keto-sulfoxide in the function of alpha-ketotioefir,

r) the conversion of carbamate into urea and, in particular, sulfonylamino in the sulfonylurea,

s) removal of protective groups, which can protect the reaction functions,

t) salt formation using mineral or organic cisisomer, enantiomers and diastereoisomers

The invention relates to compounds of the formula I, in all stereoisomeric forms and mixtures in any ratio, where NV denotes maleic acid, to a method for producing compounds of formula I, which lies in the fact that compounds of the formula II exercise anionic exchange with maleic acid and/or maleate

The invention relates to new substituted 1,2,3,4-tetrahydro-2-naphthalenamine formula I, where R1and R2independently represent hydrogen, C1-4alkyl, C1-4alkoxy, halogen, trifluoromethyl; R3represents hydrogen, hydroxyl, C1-4alkoxyl, cyano, carbarnoyl; R4and R5independently represent hydrogen, C1-4alkyl, hydroxy2-4alkyl, or form together with the nitrogen atom to which they are attached, piperidine; in the form of free bases or salts obtained by attaching acid

The invention relates to medicine, namely to surgery, and can be used for the treatment of diabetic angiopathies of the lower extremities

The invention relates to medicine

The invention relates to new naphtylpropionate F.-ly (I), where R1and R2- N, -HE or-O(C1-C4-alkyl); R3- 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholinyl, dialkylamino - or 1-hexamethylen-aminogroup; n = 2 or 3, or pharmaceutically acceptable salts
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