Benzoyl guanidines, method for their preparing, medicinal agent comprising thereof and method for treatment and prophylaxis of diseases

FIELD: organic chemistry, medicine, cardiology, biochemistry.

SUBSTANCE: invention relates to benzoyl guanidines of the formula (I): wherein R1 means -CF3; R2 means -Y-para-(C6H4)-R11, -Y-meta-(C6H4)-R11 or -Y-ortho-(C6H4)-R11 wherein R11 means (C1-C9)-heteroaryl comprising two or more nitrogen atoms adjoining across nitrogen (N) atom; Y means oxygen atom; R3 means hydrogen atom; R4 means (C1-C4)-alkyl, and to their pharmaceutically acceptable salts. Indicated compounds elicit very high activity with respect to inhibition of Na+/H+ exchange and improved water solubility and therefore they can be used as anti-arrhythmic medicinal agents with cardioprotective component for prophylaxis of infarction and treatment of infarction and for treatment of stenocardia. Also, proposed compounds inhibit pathophysiological processes in arising disorders induced by ischemia, in particular, in treatment of cardiac arrhythmia induced by ischemia.

EFFECT: improved preparing method, improved treatment and prophylaxis, valuable medicinal properties of compounds.

17 cl, 2 ex

 

The invention relates to benzoylpyridine formula I,

where mean:

R1 is hydrogen, F, Cl, Br, I, NO2CN, -Xo-(CH2)p-(CF2)q-CF3R5-SOm, R6-CO-, R6R7N-CO - or R6R7N-SO2-;

X is oxygen, -S, or NR14;

m is zero, 1 or 2;

o zero or 1;

p is zero, 1 or 2;

q zero, 1, 2, 3, 4, 5 or 6;

R5 and R6

independently from each other (C1-C8)-alkyl, (C3-C6)-alkenyl, -CnH2n-R8 or CF3;

n is zero, 1, 2, 3 or 4;

R8 (C3-C7-cycloalkyl or phenyl,

unsubstituted or substituted by 1-3

substituents selected from the group consisting of F, Cl, CF3, methyl, metoxygroup and NR9R10;

R9 and R10

N or (C1-C4)-alkyl;

or

R6 is hydrogen;

R7 hydrogen or (C1-C4)-alkyl;

or R6 and R7

together can mean 4 or 5 methylene groups, of which one CH2-group may be replaced by oxygen, S, NH, N-CH3or N-benzyl;

R2-Y-pair-(C6H4)-R11, -Y -, meta-(C6H4)-R11 or-Y-ortho-(C6H4)-R11;

R11 (C1-C9-heteroaryl, which is attached via C or

N and which is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3CH3, methoxy-, hydroxy-, amino-, methylamino, dimethylaminopropyl and Ben the sludge;

Y is oxygen, S or NR12;

R12 is H or (C1-C4)-alkyl;

R3 is as defined in R1;

or R3 (C1-C6)-alkyl or-X-R13;

X is oxygen, -S, or NR14;

R14 H or (C1-C3)-alkyl;

R13

N, (C1-C6)-alkyl, (C3-C8-cycloalkyl or-CbH2bR15;

b is zero, 1, 2, 3 or 4;

R15

phenyl which is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, metoxygroup and NR9R10;

R9 and R10

N or (C1-C4)-alkyl;

or R13 and R14

together mean 4 or 5 methylene groups, of which one CH2-group may be replaced by oxygen, S, NH, N-CH3or N-benzyl;

R4 is F, Cl, Br, I or (C1-C4)-alkyl;

and their pharmaceutically acceptable salts.

Preferred compounds of formula I, where mean:

R1 is hydrogen, F, Cl, CN, CF3R5-SOm-, R6-CO-, R6R7N-CO - or R6R7N-SO2-;

m is zero, 1 or 2;

R5 and R6

independently from each other (C1-C8)-alkyl, (C3-C4)-alkenyl, -CnH2n-R8 or CF3;

n is zero or 1;

R8 (C3-C6-cycloalkyl or phenyl,

which is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, metoxygroup and NR9R10;

R9 and R10

R9 and R10 is H or methyl; or

R6 is hydrogen;

R7 hydrogen or methyl;

R2-Y-pair-(C6H4)-R11, -Y-m is TA-(C 6H4)-R11 or-Y-ortho-(C6H4)-R11;

R11 (C1-C9-heteroaryl, which is attached via C or

N and which is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3CH3, methoxy-, hydroxy-, amino-, methylamino, dimethylaminopropyl and benzyl;

Y is oxygen, S or NR12;

R12 is H or (C1-C4)-alkyl;

R3 is hydrogen, methyl, CN, CF3, F or Cl;

R4 is F, Cl or (C1-C4)-alkyl;

and their pharmaceutically acceptable salts.

Particularly preferred compounds I in which mean:

R1 is hydrogen, F, Cl, CN, CF3or R5-SOm-;

m is zero, 1 or 2;

R5 methyl or CF3;

R2-Y-pair-(C6H4)-R11, -Y -, meta-(C6H4)-R11 or-Y-ortho-(C6H4)-R11;

R11 (C1-C9-heteroaryl, which is attached via C or N and which is not substituted or is substituted by 1-2 substituents selected from the group consisting of F, Cl, CF3CH3, methoxy-, dimethylaminopropyl and benzyl;

Y is oxygen;

R3 is hydrogen, methyl, CN, CF3, F or Cl;

R4 (C1-C4)-alkyl;

and their pharmaceutically acceptable salts.

In particular, preferred compounds of formula I, where

R1 is hydrogen, F, Cl, CN, CF3or R5-SO2-;

R5 methyl or CF3;

R2-Y-pair-(C6H4)-R11, -Y -, meta-(C6H4)-R11 or-Y-ortho-(C6H4/sub> )-R11;

R11 (C1-C5-heteroaryl, which is attached via C or

N and which is not substituted or is substituted by 1 or 2 substituents selected from the group consisting of F, Cl, CF3CH3, methoxy-, dimethylaminopropyl and benzyl;

Y is oxygen;

R3 is hydrogen;

R4 (C1-C4)-alkyl;

and their pharmaceutically acceptable salts.

Especially preferred compounds of formula I, where mean:

R1 CF3;

R2-Y-pair-(C6H4)-R11, -Y -, meta-(C6H4)-R11 or-Y-ortho-(C6H4)-R11;

R11 imidazolyl or triazolyl, which is not substituted or

substituted by 1 or 2 substituents selected from the group consisting of F, Cl, CF3CH3, methoxy-, dimethylaminopropyl and benzyl;

Y is oxygen;

R3 is hydrogen;

R4 is methyl;

and their pharmaceutically acceptable salts.

These alkyl residues may be both linear and branched.

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

As Goethe is of aurila take into account furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazoles, hinely, ethanolic, phthalazine, honokalani, hintline, cinnoline; especially furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, pyridyl, indolyl, chinosol and ethanolic.

The advanced invention relates to a production method of compound I, wherein compound of formula II

where R1-R4 have the above values, a L is tsepliaeva group capable of easy nucleophilic substitution, is subjected to the interaction with guanidine.

The activated acid derivative of formula II, where L is alkoxy, preferably a methoxy group, fenoxaprop, phenylthio-, methylthio-, 2-pyridylthio, nitrogen-containing heterocycle, preferably 1-imidazolyl, receive, preferably in a known manner from the corresponding acid chlorides of carboxylic acids (formula II, L=Cl), which in turn can be obtained in a known manner from the corresponding carboxylic acids (formula II, L=OH), for example, with thionyl chloride.

Along with carboxylic acid anhydrides of the formula II (L=Cl), there is also the opportunity to get other activated acid derivatives of the shape of the s II in a known manner directly from the corresponding derivatives of benzoic acid (formula II, L=OH), such as methyl ether of the formula II with L=OCH3by treating with gaseous HCl in methanol; imidazoline formula II by treatment with carbonyl diimidazol [L=1-imidazolyl, Staab, Angew. Chem. Int. Ed. Engl.1, 351-367 (1962)], the mixed anhydride II with Cl-COOC2H5or mozillateam in the presence of triethylamine in an inert solvent, as well as the activation of benzoic acid dicyclohexylcarbodiimide (DCC) or tetrafluoroborate O-[(cyano(etoxycarbonyl)methylene)amino]-1,1,3,3-tetramethyluronium ("TOTU") [Proceedings of the 21. European Peptide Symposium, Peptides 1990, Editors E. Giralt and Andreu, Escom, Leiden, 1991]. A number of suitable methods for obtaining activated derivatives of carboxylic acids of formula II listed in the references list in J.March, Advanced Organic Chemistry, third edition (John Wiley & Sons, 1985), p.350.

The interaction of activated carboxylic acid derivative of the formula II with guanidine carried out in a known manner in proton or aprotic polar but inert organic solvent. Moreover, the interaction of the methyl ester of benzoic acids (II, L=OMe) with guanidine was suitable methanol, isopropanol or THF at 20°C to the boiling temperature of these solvents. Most reactions of compounds II with the free guanidine salts is preferably carried out in aprotic inert solvents such as THF, dimethoxyethane, dioxane. But PR is the use of reason, as for example NaOH, the reaction of compound II with guanidine as a solvent can be used is water.

If L=Cl, preferably add catcher acid, for example, in the form of excess guanidine binding halogenation acid.

Of the corresponding derivatives of benzoic acid of the formula II are known and described in the literature. Unknown compounds of formula II can be obtained by methods known from the literature. Received benzoic acid were transformed to obtain the compounds I according to the invention in one of the above described variants of the method.

The introduction of certain substituents in the 2, 3-, 4 - and 5-position is possible by known literature methods cross-combination of aryl halides or aritifical with, for example, organosilane, organoboronic acids or organoboranes or copper - or zinc-organic compounds via palladium.

Benzoylpyridine I usually are weak bases and can bind the acid with the formation of salts. As additive salts of acids talking about all pharmacologically acceptable salts, such as halides, in particular, hydrochloride, lactates, sulfates, citrates, tartratami, acetates, phosphates, methylsulfonate, toluensulfonate.

The compounds I are replaced by arylguanidines

Compounds similar to the compounds I are known from European application 640593 (NOAH 93/F 220). However, these compounds contain as substituents only R4 (in ortho-position), instead of the other deputies; the compounds according to the invention there is neither mentioned nor recommended.

In contrast to the known compounds of the proposed compounds exhibit extremely high activity against inhibition of Na+/N+-sharing, and improved solubility.

Proposed connection as well as the known compounds are not harmful solidarities properties, but have a very good antiarrhythmic properties; for example, they are important for the treatment of diseases that come with symptoms of oxygen deficiency. Connection due to their pharmacological properties suitable as antiarrhythmic drugs with a cardioprotective component for the prophylaxis of infarction and treatment of infarction and for the treatment of angina pectoris, where they also inhibit or greatly reduce the pathophysiological processes in the emergence of induced ischemia disorders, in particular, when liquidation is initiated by ischemia of cardiac arrhythmias. Due to their protective effects against pathological hypoxic and ischemic events predlagaemaya formula I may, because of the inhibition mechanism of cellular Na +/N+-the currency to be used as medicines for the treatment of all acute or chronic, caused by ischemia disorders or primary or secondary induced ischemia diseases. This applies to their use as medicines during surgery, for example, organ transplantation, and the connections of the applicable both to protect the organ from the donor before and during the separation, for the protection of separated body, for example, processing or storage in physiological fluids and transplantation in the recipient's organism. Compounds are also valuable protective drugs when conducting angioplasticheskih operations, for example, heart or peripheral vessels. In accordance with their protective effect against induced ischemia violations of applicable connection as well as medicines for the treatment of ischemia of the nervous system, particularly the Central nervous system, where they are applicable, for example, for treatment of a stroke or cerebral edema. Moreover, we offer you the compounds of formula I are also applicable for the treatment of various forms of shocks, as, for example, of allergic, cardiogenic, hypovolemic and bacterial shock. Further, the compounds of formula I exhibit a strong inhibitory effect on the proliferation of cells, for example, kletocna the proliferation of fibroblasts and proliferation of smooth muscles. So we are talking about the compounds of formula I as valuable therapeutic tools for diseases in which cell proliferation represents a primary or secondary cause, and therefore applicable as antiatherosclerotic funds funds against late diabetic complications, cancerous diseases, fibrotic diseases such as pulmonary fibrosis, fibrosis of the liver or kidney fibrosis, hypertrophy and hyperplasia of the authorities, in particular in prostate hyperplasia or hypertrophy of the prostate.

The proposed compounds are effective inhibitors of the cellular sodium-proton exchange (Na+/H+-exchangers), which in numerous diseases (essential hypertension, atherosclerosis, diabetes etc) increased in these cells, which are easily accessible to measurements, such as, for example, in erythrocytes, platelets or leukocytes. The proposed connection is therefore applicable as a simple scientific tools, for example, to identify and distinguish the forms of hypertension, but also of atherosclerosis, diabetes, proliferative diseases, etc. moreover the compounds of formula I is applicable for preventive therapy to prevent the Genesis of high blood pressure, for example, essential hypertension.

In addition, we discovered that the compounds of formula I have a favorable effect on vortochny lipoproteins. Generally recognized that the emergence of atherosclerotic changes in blood vessels, particularly coronary heart disease, a major risk factor is too high lipid levels in the blood, the so-called hyperlipoproteinemia. For the prevention and regresi atherosclerotic changes of exceptional importance is the reduction of elevated serum lipoprotein. Along with a decrease in total serum cholesterol of particular importance is the decrease in the proportion of specific atherogenic lipid fractions such total cholesterol, particularly low density lipoprotein (LDL) and lipoprotein very low density (VLDL), as these lipid fractions are atherogenic risk factor. On the contrary, high-density lipoprotein attributed to a protective effect against coronary heart disease. Accordingly, lipid-lowering means should provide a reduction not only of cholesterol, but in particular VLDL - and LDL-fraction of serum cholesterol. It is shown that the compounds of formula I are valuable therapeutic properties regarding the influence on the level of serum lipids. So, they significantly reduce the increased concentration of LDL and VLDL, which is observed, for example, with the increased introduction in the diet of foods rich in cholesterol and lipids, or when patol the technological changes of metabolism, for example, when genetically hyperlipidemia. Therefore they can be employed for the prevention and regresi atherosclerotic changes, thus precluding causal risk factor. This includes not only the primary hyperlipidemia, but also known secondary hyperlipidemia, as, for example, coming in diabetes. Moreover the compounds of formula I leads to a clear reduction anomalies of metabolism-induced heart attack, and, in particular, to a noticeable reduction induced extensive infarction and its severity. Additionally, the compounds of formula I effective in protecting against violations of endothelium induced abnormalities of metabolism. Thanks to this protection of the vessels against the syndrome of endothelial dysfunction of the compounds of formula I are valuable drugs for the prevention and treatment of spasms of the coronary vessels, atherogenesis and atherosclerosis, levobetaxolol hypertension and dilated cardiomyopathy and thrombotic diseases.

These compounds therefore are preferably used to produce medicines for the treatment of hypercholesterolemia; to obtain drugs for the prevention of atherogenesis; to obtain drugs for the prevention and treatment of atherosclerosis, for which Holocene medicines for the prevention and treatment of diseases, caused by the high cholesterol level; to obtain medicines for preventing and treating diseases caused by endothelial dysfunction; to obtain drugs for prevention and treatment-induced atherosclerosis hypertension; to obtain drugs for prevention and treatment-induced atherosclerosis thrombosis; to obtain drugs for prevention and treatment of ischemic disorders and postischemic reperfusion disorders induced by hypercholesterolemia and endothelial dysfunction; to obtain drugs for prevention and treatment of cardiac hypertrophy and cardiomyopathy induced hypercholesterolemia and endothelial dysfunction; to obtain drugs for prevention and treatment of spasms of the coronary vessels and myocardial infarction induced by hypercholesterolemia and endothelial dysfunction; to obtain drugs for the treatment of these diseases in combination with hypotensive substances, preferably with angiotensin converting enzyme inhibitors (ACE) and antagonists angiotensinogen receptors. The combination of the compounds of formula I with a substance decreasing the level of blood lipids, preferably with inhibitor HM-CoA-reductase (for example, with lovastatin or pravastatin), giving additional hypolipidemic effect and increases lipid-lowering properties of Na+/N+inhibitor of formula I, is a favorable combination with intensified action and reduced by the introduction of active substances.

The proposed introduction of inhibitors of Na+/N+-sharing formula I as new drugs for lowering elevated blood lipids, and combinations of inhibitors of Na+/H+-exchange with antihypertensive and/or lipid-lowering drugs.

Medicines that contain compound I may be administered orally, intravenously, rectally or by inhalation, preferably the introduction depends on the picture of this disease. The compounds I can be used individually or together with galenovye auxiliary substances both in veterinary and in human medicine.

What excipients are applicable for the desired pharmaceutical compositions known to the expert based on his special knowledge. Along with solvents, geleobrazovanie, the basics of suppositories, tabletiruemye auxiliary substances and other carriers of active substances can be used, for example, antioxidants, dispersing agents, emulsifiers, foaming agents, corre the Torah taste, preservatives, soljubilizatory or dyes.

For oral forms of application active substance is mixed with suitable additives, such as carriers, stabilizers or inert diluents, and the usual ways to turn in the desired form of application, such as tablets, coated tablets, sealed capsules, aqueous, alcoholic or oily solutions. As the inert carrier is applicable, for example, gum Arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch. Moreover, the composition can be represented both as dry and as wet granules. As an oil carrier or solvent can be considered, for example, vegetable or animal fats, such as sunflower oil or cod-liver oil.

For subcutaneous or intravenous administration, the active compounds, if desired with conventional substances such as soljubilizatory, emulsifiers or other auxiliaries, contribute to the solution, suspension or emulsion. As a solvent it is, for example, water, physiological saline or alcohol, for example ethanol, propanol, glycerol, and in addition, solutions of sugars, such as glucose or mannitol, or a mixture of various of the aforementioned solvents.

As a pharmaceutical preparation for use in the form of the of erotola or sprays are suitable, for example, solutions, suspensions or emulsions of the active substances of the formula I in a pharmaceutically acceptable solvents, such as, in particular, ethanol or water, or in mixtures of such solvents.

Drugs on demand can also contain other pharmaceutical excipients such as surfactants, emulsifiers and stabilizers, as well as the carrier gas. Such preparations contain the active substance is usually in a concentration of from about 0.1 to 10, in particular from about 0.3 to 3 wt.%.

Dosage enter the active substance of the formula I and the frequency of introduction depends on the activity and duration of action of the compounds used; additionally, on the type and severity of treatable diseases, as well as gender, age, weight and sensitivity of the treated mammal.

The average daily dose of the compounds of formula I with a weight of 75 kg is at least 0,mg/kg, preferably at least 0.01 mg/kg, in particular at least 0.1 to at most 10 mg/kg, preferably at most to 1 mg/kg of body weight. In acute forms of the disease, possibly immediately after the transfer of myocardial infarction, may need even higher and especially more frequent dosing, for example up to 4 individual doses per day. In particular, when administered intravenously to patients what Parkton may be necessary intensity to 200 mg per day.

List of abbreviations:

CDIcarbonyldiimidazole
Meonmethanol
DMFN,N-dimethylformamide
count-RAroom temperature
EEthe ethyl acetate
EQ.equivalent to
ESelectrospray ionization

Experimental part

Example 1

The dihydrochloride of 4-[(imidazol-1-yl)phenoxy]-2-methyl-5-trifluoromethyl-benzoylpyridine, colourless solid, M++H(ES)=404

Method of delivery:

a) Methyl ester of 4-[(imidazol-1-yl)phenoxy]-2-methyl-5-trifluoromethyl-benzoic acid is obtained by reaction of methyl ester of 4-fluoro-2-methyl-3-trifluoromethyl-benzoic acid with 1 EQ. 4-(imidazol-1-yl)phenol in the presence of 4 equiv. potassium carbonate in DMF at 120°C for 16 hours. After evaporation of the solvent is treated with water and shaken out with EE. After drying evaporated the solvent, a colorless oil, M+(ES)=376.

b) 4-[(imidazol-1-yl)phenoxy]-2-methyl-5-trifluoromethyl-benzoic acid is subjected to alkaline hydrolysis with excess 2n. aqueous NaOH in the Meon at room temperature for 2 hours. After acidification 2n. HCl followed by extraction uh, after drying dissolve the I and evaporation falls colorless oil, M+(ES)=362.

The dihydrochloride of 4-[(imidazol-1-yl)phenoxy]-2-methyl-5-trifluoromethyl-benzoylpyridine activated using 2 EQ. CDI in DMF and subsequent reaction with 6 copies of guanidine hydrochloride in the presence of 7 EQ. diisopropylethylamine at room temperature for 3 hours. After removal of the solvent spend preparative HPLC (CH3CN/H2O), followed by salt formation with hydrochloric acid in a mixture with ether.

Example 2.

Bis-triptorelin 4-(triazole-1-yl)phenoxy-2-methyl-3-trifluoromethyl-benzoylpyridine, colourless solid, M++H(ES)=405.

Method of delivery:

a) methyl ester of 4-[(triazole-1-yl)phenoxy]-2-methyl-5-trifluoromethyl-benzoic acid get similarly 1A) by reaction with 1 equiv. 4-(triazole-1-yl)phenol, colorless oil, M+(ES)=377.

b) 4-[(triazole-1-yl)phenoxy]-2-methyl-5-trifluoromethyl-benzoic acid is obtained analogously 16), colorless oil, M+(ES)=363.

C) bis-triptorelin 4-[(triazole-1-yl)phenoxy]-2-methyl-5-trifluoromethyl-benzoylpyridine get similar 1B), however, the salt formation is carried out using triperoxonane acid. It is established that the compound of example 1 of the formula:

has inhibitory activity, which is characterized by the value of the IC50=7,7 nm.

1. Benzoylpyridine formula I,

where mean

R1 CF3;

R2-Y-para-(C6H4)-R11, -Y -, meta-(C6H4)-R11 or-Y-ortho-(C6H4)-R11;

R11 (C1-C9-heteroaryl containing two or more nitrogen atoms, attached through N;

Y is oxygen;

R3 is hydrogen;

R4 (C1-C4)-alkyl;

and their pharmaceutically acceptable salts.

2. The compounds of formula I according to claim 1, where the mean R1 CF3; R2-Y-pair-(C6H4)-R11, -Y -, meta-(C6H4)-R11 or-Y-ortho-(C6H4)-R11; R11 (C1-C5-heteroaryl containing two or more nitrogen atoms, attached through N; Y is oxygen; R3 is hydrogen; R4 (C1-C4)-alkyl; and their pharmaceutically acceptable salts.

3. The compounds of formula I according to claim 1 or 2, where the mean R1 CF3; R2-Y-pair-(C6H4)-R11, -Y -, meta-(C6H4)-R11 or-Y-ortho-(C6H4) -R11; R11 imidazolyl or triazolyl; Y is oxygen; R3 is hydrogen; R4 is methyl; and their pharmaceutically acceptable salts.

4. Method of producing compounds of the formula I, characterized in that the compound of formula II,

where residues from R1 through R4 have the values specified in claim 1, and L means easy nucleophile replaced tsepliaeva group, is subjected to the interaction with guanidine.

5. The compounds I according to claim 1, distinguishing the I, what is suitable for obtaining a medicinal product for the treatment or prevention of diseases caused by ischemic condition.

6. Method for the treatment and prevention of diseases caused by ischemic condition, characterized in that an effective amount of a compound I according to claim 1 is mixed with conventional additives and injected into a suitable form for the application.

7. The compounds I according to claim 1, characterized in that suitable for the production of pharmaceuticals for the treatment and prevention of myocardial infarction and arrhythmias.

8. The compounds I according to claim 1, characterized in that suitable for the production of pharmaceuticals for the treatment or prophylaxis of angina.

9. The compounds I according to claim 1, characterized in that suitable for the production of pharmaceuticals for the treatment or prophylaxis of ischemic conditions of the heart.

10. The compounds I according to claim 1, characterized in that suitable for the production of pharmaceuticals for the treatment or prophylaxis of ischemic conditions of the peripheral and Central nervous system and stroke.

11. The compounds I according to claim 1, characterized in that suitable for the production of pharmaceuticals for the treatment or prophylaxis of ischemic conditions of peripheral organs and limbs.

12. The compounds I according to claim 1, characterized in that suitable to obtain medicines for mechanismwhich States.

13. The compounds I according to claim 1, characterized in that suitable for medicinal products for introduction in surgical operations and organ transplants.

14. The compounds I according to claim 1, characterized in that suitable to obtain drugs for preservation and storage of transplants for surgical events.

15. The compounds I according to claim 1, characterized in that suitable for the production of medicines for the treatment of diseases in which cell proliferation is a primary or secondary cause.

16. The compounds I according to claim 1, characterized in that suitable for the production of pharmaceuticals for the treatment or prevention of metabolic disorders.

17. Pharmaceutical drug that will inhibit Na+/H+-currency, characterized in that it contains an effective amount of a compound I according to one of claims 1 to 3.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of imidazole of the formula (I):

or its pharmaceutically acceptable salts wherein X represents -CH2-(CH2)p-, -O-; R1 represents phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, (C3-C7)-cycloalkyl wherein indicated phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, (C3-C7)-cycloalkyl are substituted optionally with 1-3 substitutes taken independently among halogen atom, -OH, halogen-(C1-C6)-alkyl, (C1-C6)-alkyl, (C1-C6)-alkoxy group and OH-(C1-C6)-alkyl; R2 represents hydrogen atom (H) or (C1-C6)-alkyl; R3 represents H or (C1-C6)-alkyl; R4 represents H or (C1-C6)-alkyl; R5 represents H, or R5 and R7 form in common a bond; each R6 represents independently halogen atom, -OH, halogen-(C1-C6)-alkyl, (C1-C6)-alkyl, (C1-C6)-alkoxy group or OH-(C1-C6)-alkyl; R7 represents H, or R7 and R5 form in common a bond; each R8 represents independently -OH, (C1-C6)-alkyl, halogen-(C1-C6)-alkyl or (C1-C6)-alkoxy group; m = 0, 1, 2 or 3; n = 0 or 1; p = 0 or 1; r = 0 or 1; t = 0. Also, invention relates to a method for preparing compounds of the formula (I) and to a pharmaceutical composition showing affinity to alpha-2-adrenoceptors based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof used in aims for treatment of neurological disturbances, psychiatric disorders or disturbances in cognitive ability, diabetes mellitus, lipolytic diseases, orthostatic hypotension or sexual dysfunction.

EFFECT: improved preparing method, valuable medicinal properties of compounds and compositions.

25 cl, 1 tbl, 14 ex

FIELD: organic chemistry, medicine, hormones.

SUBSTANCE: invention describes imidazole derivatives of the formula (I) , racemic-diastereomeric mixtures and optical isomers, pharmaceutical salts wherein ---- represents an optional bond; R1 represents hydrogen atom (H), -(CH2)m-C(O)-(CH2)m-Z1, -(CH2)m-Z1; R2 represents hydrogen atom (H), or R1 and R2 are joined with nitrogen atoms to which they are bound forming compounds represented by formulae (Ia), (Ib) or (Ic) wherein R3 represents -(CH2)m-E-(CH2)m-Z2; R4 represents hydrogen atom (H) or -(CH2)m-A1; R5 represents (C1-C12)-alkyl, (C0-C6)-alkyl-C(O)-NH-(CH2)m-Z3 and optionally substituted phenyl; R6 represents hydrogen atom (H); R7 represents (C1-C12)-alkyl or -(CH2)m-Z4; m = 0 or a whole number from 1 to 6; n is a whole number from 1 to 5. Proposed compounds bind with subtypes of somatostatin receptors selectively.

EFFECT: valuable properties of compounds.

20 cl, 13776 ex

The invention relates to new imidazole derivative of the formula (I):where R1represents phenyl or pyridinyl, substituted by substituents selected from the group comprising (1) phenyl, (2) furyl, thienyl, (3) halogen, (4) halogen(lower)alkyl, (5) lower alkylthio, (6) nitro, (7) lower alkenyl, optionally substituted phenyl, (8) lower quinil, optionally substituted phenyl, (9) lower alkoxy, optionally substituted cyclo(lower)alkyl or phenyl, (10) lower alkyl, optionally substituted, phenyloxy or (11) amino, optionally substituted protected carboxyla; R2represents lower alkyl; R3represents halogen or lower alkyl; R4represents (1) lower alkenyl, optionally substituted phenyl, (2) phenyl, optionally substituted lower alkyl or lower alkenyl, (3) lower alkyl or (4) thienyl, optionally substituted with halogen; a represents a lower alkylene and L represents a simple bond, a lower albaniles or lower alkylene, optionally substituted phenyl or pyridinyl, or-X-CH2- where X represents O or NR5where R5represents hydrogen or n is

New drug substances // 2237657
The invention relates to organic chemistry and can find application in medicine

New drugs // 2237057
The invention relates to organic chemistry and can find application in medicine

The invention relates to new and nitrate salts of heterocyclic compounds of formulas (a) and (b), where R is hydrogen, alkoxyl, R1- alkyl, alkoxyl, R2is hydrogen, alkyl, R3- alkyl, alkoxyl, X denotes N-R11or oxygen, R11means the free valence, Y represents N-R16, sulfur or alkyl, R16means hydrogen; other values radicals presented in the description of the invention

The invention relates to new derivatives of phenyl - and aminobenzenesulfonamide formula

< / BR>
where a denotes (R1SO2NR2-), (R3R60NSO2NR2-); X represents-NH-, -CH2- or-OCH2-; Y represents 2-imidazoline, 2-oxazoline or 4-imidazole; R1means (NISS

The invention relates to the derivatives of dihydronaphthalene formula I, where R1represents hydrogen, hydroxyl or alkyloxy, R2represents hydrogen, lower alkyl, aralkyl or phenyl, and R3represents pyridyl or imidazolyl

The invention relates to new compounds having formula I or formula II:

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where R1represents H, lower alkylthio or R1together with R2form a-CH2-; each of R2and R3independently represents H or lower alkyl; R4represents Oh or H2; R5is H, unsubstituted lower alkyl, cyclohexyl - lower alkyl; each of R6and R7independently represents hydrogen, phenyl, naphthyl, -C(O)-NHCHR13CO2R14or substituted phenyl, where the Deputy represents halogen, lower alkyl, lower alkoxy, hydroxy, or phenyl - lower alkoxy; R8represents H or lower alkyl; R9represents H or lower alkyl; R12is NR9or S; R13is lower alkylthio; R14represents H or lower alkyl; or their pharmaceutically acceptable salts, with the exception of 4,5-bis(4-methoxyphenyl)-2-(4-thiazolidinediones)thiazole and its hydrochloride

The invention relates to new amide derivatives of General formula (I) or their salts, where a means thiazolidin, imidazoline, triazoline, benzimidazolyl, benzothiazolyl, thiadiazolyl, imidazopyridine or imidazothiazole; X is a bond, -NR5-, -NR5CO-, -NR5CONH-, NR5SO2-, -NR5C(= NH)NH-; R1means H, lower alkyl, aryl, pyridyl, thienyl, furyl, thiazolyl, benzimidazolyl, imidazopyridine, triazolyl, thiadiazolyl, imidazolyl, imidazothiazoles, benzothiazolyl, cyclohexyl, which may be optionally substituted with halogen, lower alkyl, -OH, -CN, -NO2, -CF3, -NH2, -O-lower alkyl, and the Deputy of the lower alkyl may be substituted by phenyl, naphthyl, fullam, tanila or pyridium;2a, R2bmean H or lower alkyl; R3means hydrogen or lower alkyl; R4a, R4bmean H or HE, or taken together form a group =O or =N-O-lower alkyl; R5means H or lower alkyl

FIELD: medicine.

SUBSTANCE: method involves applying intracoronary phosphocreatine introduction into infarction-responsible artery when carrying out coronary angioplasty. Phosphocreatine solution is injected after reperfusing the infarction-responsible artery at constant volume rate of 0.1-4 ml/s with introduced phosphocreatine dose being equal to 0.5-4 g.

EFFECT: reduced myocardium necrosis zone; prevented cardiac insufficiency and cardiac rhythm disorders.

4 cl

FIELD: organic chemistry, chemical technology, medicine, biochemistry.

SUBSTANCE: invention relates to quinuclidine compounds of the formula (I) , its salts or their hydrates wherein R1 represents hydroxyl group; W represents: (1) -CH2-CH2-; 2) -CH=CH-, or 3) -C≡C-; HAr represents 5-10-membered aromatic heterocycle comprising 1-2 heteroatoms taken among nitrogen atom and sulfur atom that in addition to the group -X-Ar can be substituted with 1-3 groups taken among: (1) halogen atom; (2) (C1-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-alkynyl group substituted optionally with: (a) hydroxy-group; (b) (C1-C6)-alkoxycarbonyl; (c) (C1-C6)-alkanoyl optionally substituted with (C1-C6)-alkoxy-group; (d) hydroxylated (C3-C8)-cycloalkyl; (e) (C1-C6)-alkoxy-group; (f) 5-6-membered aromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom, or (g) cyano-group; (3) (C1-C6)-alkoxy-group optionally substituted with: (a) hydroxy-group; (b) (C1-C6)-alkoxy-group optionally substituted with (C1-C6)-alkoxy-group; (c) halogen atom; (d) 4-6-membered nonaromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom; (e) 5-6-membered aromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom; (4) (C1-C6)-alkylthio-group optionally substituted with (C1-C6)-alkoxy-group or hydroxy-group; (5) 5-6-membered heterocyclyloxy-group comprising 1-2 oxygen atoms in heterocycle; (6) amino-group represented by the formula: -N(R3)R4 wherein R3 and R4 are similar or different and each represents hydrogen atom or group taken among: (a) (C1-C6)-alkyl group; (b) (C1-C6)-alkoxy-(C1-C6)-alkyl group; (c) carbonyl substituted with (C6-C14)-aryl; (d) (C6-C14)-arylsulfonyl or (e) 4-6-membered nonaromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom; (7) (C3-C8)-cycloalkyl or cycloalkenyl hydrocarbon group optionally substituted with: (a) oxo-group or (b) hydroxy-group; (8) (C6-C14)-aromatic hydrocarbon ring optionally substituted with: (a) (C1-C4)-alkylene dioxy-group or (b) hydroxy-group; (9) 5-6-membered aromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom optionally substituted with: (a) cyano-group or (b) (C1-C6)-alkoxy-group; (10) 4-6-membered nonaromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom optionally substituted with one or some groups taken among: (a) hydroxy-group; (b) halogen atom; (c) cyano-group; (d) (C1-C6)-alkoxycarbonyl; (e) (C1-C6)-alkyl; (f) (C1-C6)-alkoxy-group that is optionally substituted with halogen atom or (C1-C6)-alkoxy-group; (g) (C1-C6)-alkanoyl; (h) (C1-C6)-alkoxy-(C1-C6)-alkyl; (i) oxo-group; (j) (C1-C4)-alkylenedioxy-group; (k) (C3-C8)-cycloalkylalkoxy-group or (C3-C8)-cycloalkenylalkoxy-group; (11) carbamoyl of the formula: -CO-N(R5)R6 wherein R5 and R6 can be similar or different and represent hydrogen atom, (C6-C14)-aryl wherein indicated aryl is optionally substituted with halogen atom, or (C3-C8)-cycloalkyl; or R5 and R6 form in common 3-6-membered ring; (12) carbonyl optionally substituted with (C1-C6)-alkoxy-group; X represents: (1) a simple bond; (2) (C1-C6)-alkylene chain; (3) (C1-C6)-alkenylene chain; (4) (C1-C6)-alkynylene chain; or (5) formula: -Q- wherein Q represents oxygen atom or sulfur atom; Ar represents: (1) (C6-C14)-aromatic hydrocarbon ring optionally substituted with one or some groups taken among: (a) halogen atom; (b) (C1-C4)-alkoxy-group or (c) (C1-C6)-alkylthio-group; or (2) 5-6-membered aromatic heterocycle comprising 1-2 heteroatoms taken among nitrogen atom and sulfur atom. Compounds of the formula (I) show inhibitory activity with respect to a squalene-synthesizing enzyme. Also, the invention relates to an inhibitor of squalene-synthesizing enzyme and the corresponding medicinal composition based on compound of the invention, a method for prophylaxis and treatment of disease wherein inhibition of squalene-synthesizing enzyme is effective. Also, invention proposes some methods for preparing compounds of the formula (I).

EFFECT: improved preparing method, valuable of medicinal and biochemical properties of com[pounds and composition.

25 cl, 10 tbl, 214 ex

FIELD: medicine.

SUBSTANCE: method involves administering a combination of an agent reducing cholesterol content in blood and reduced coenzyme Q10 of general formula .

EFFECT: enhanced effectiveness of treatment.

8 cl, 2 tbl

FIELD: medicine, cardiology.

SUBSTANCE: the present innovation deals with introducing nitrates, heparin, beta-blocking agents, calcium antagonists, aspirin. Additionally, one should intravenously inject dalargin once daily at the rate of about 5-7 mcg/kg/h at the dosage of 25-30 mcg/kg daily per 100 ml sodium chloride physiological solution for about 5-6 d against the onset of hospitalization period. The innovation provides favorable impact upon diastolic function of left ventricle by decreasing the risk of dangerous arrhythmias and coronary lethality.

EFFECT: higher efficiency of therapy.

2 ex

FIELD: medicine, cardiology.

SUBSTANCE: one should introduce the suspension of autologous mononuclear medullary cells without preliminary cultivation in to the mouth of coronary artery nourishing infarction area. Cell suspension should be introduced at the quantity of 100-150 mln. cells immediately after stenting coronary artery due to technique of passive passage. The procedure should be performed on the 14th - 21st d against the onset of the disease mentioned. The method provides efficient counterbalance of cardiomyocytes due to applying valuable stem cells at excluding complications induced by arterial occlusion.

EFFECT: higher efficiency of therapy.

1 ex, 1 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of triazaspiro[5,5]undecane of the formula (I):

wherein values of radicals R1-R5 are given in the invention claim, ort o their quaternary ammonium salts, N-oxides or nontoxic salts. Proposed compounds possess inhibitory and regulating activity with respect to chemokine/chemokine receptors and can be useful in prophylaxis and treatment of different inflammatory diseases, such as asthma, atopic dermatitis, nettle rash, allergic diseases, nephritis, hepatitis, arthritis or proliferative arthritis and other similar diseases. Also, invention relates to pharmaceutical compositions based on compounds of the formula (I).

EFFECT: improved control method, valuable medicinal properties of compounds.

9 cl, 5 sch, 36 tbl, 70 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new nitrogen-containing aromatic derivatives of the general formula:

wherein Ag represents (1) group of the formula:

; (2) group represented by the formula:

or ; (3) group represented by the formula:

; Xg represents -O-, -S-, C1-6-alkylene group or -N(Rg3)- (wherein Rg3 represents hydrogen atom); Yg represents optionally substituted C6-14-aryl group, optionally substituted 5-14-membered heterocyclic group including at least one heteroatom, such as nitrogen atom or sulfur atom, optionally substituted C1-8-alkyl group; Tg1 means (1) group represented by the following general formula:

; (2) group represented by the following general formula: . Other radical values are given in cl. 1 of the invention claim. Also, invention relates to a medicinal agent, pharmaceutical composition, angiogenesis inhibitor, method for treatment based on these compounds and to using these compounds. Invention provides preparing new compounds and medicinal agents based on thereof in aims for prophylaxis or treatment of diseases wherein inhibition of angiogenesis is effective.

EFFECT: improved treatment method, valuable medicinal properties of compounds and agents.

40 cl, 51 tbl, 741 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention concerns a new oral formulation of the galenic preparation molsidomine with prolonged releasing an active substance and designated in treatment of stenocardia attack in all its variations (stress stenocardia, spastic stenocardia, nonstable stenocardia). This novel formulation of galenic preparation comprises the therapeutically effective dose of molsidomine or one of its active metabolites and shows the following dissolving rate values in vitro [measured by spectrophotometry method at wavelength 286 or 311 nm according to a method reported in Pharmacopee Europeene, 3-d edition (or U. S. P. XXIV) at 50 rev./min in 500 ml of medium consisting of 0.1 N HCl at 37°C]: 15-25% of molsidomine released in 1 h; 20-35% of molsidomine released in 2 h; 50-65% of molsidomine released in 6 h; 75-95% of molsidomine released in 12 h; >85% of molsidomine released in 18 h, and >90% of molsidomine released in 24 h wherein the maximal blood plasma concentration of molsidomine in vivo appears in 2.5-5 h but preferably in 3-4 h after intake of abovementioned formulation and has value from 25 to 50 ng/ml of blood plasma. Invention provides reducing amount of doses of drug per a day that is more suitable for a patient.

EFFECT: improved and valuable pharmaceutical properties of preparation.

14 cl, 5 dwg, 2 tbl, 7 ex

FIELD: medicine, phytotherapy, pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to using Belamcanda chinensis extract for preparing organ-selective medicinal preparation without uterotropic effect or with minimal such effect that is used as estrogen-like preparation. This preparation is used in selective treatment and/or prophylaxis of cardiovascular diseases, in particular, atherosclerosis and osteoporosis, climacteric disturbances, especially for prophylaxis or softening congestions of blood. Extract is used in manufacturing a medicinal preparation in ready formulation for selective treatment and/or prophylaxis of cardiovascular diseases, in particular atherosclerosis, and for selective treatment and/or prophylaxis of osteoporosis, climacteric disturbances, especially for prophylaxis and softening congestions of blood. Extract promotes to effective prophylaxis and/or treatment of cardiovascular diseases, in particular, atherosclerosis, climacteric disturbances, especially for prophylaxis and softening congestions of blood.

EFFECT: valuable medicinal properties of extract.

4 cl, 4 ex

FIELD: medicine, neurology.

SUBSTANCE: the present innovation deals with treating cerebral vascular diseases accompanied with psychic disorders. For this purpose one should introduce homeopathic preparations named Cerebrum compositum and Hepar compositum per 2.2 ml every other day for 20 d intramuscularly, and beginning since the 11th d one should additionally prescribe Vertigohel preparation per 10 drops thrice daily for 10 d. The innovation suggested provides decreased different psychotic and unpsychotic depressive syndromes that considerably improves quality of life in this category of patients.

EFFECT: higher efficiency of therapy.

2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: the suggested pharmaceutical composition contains 2-ethylthiobenzimidasol hydrobromide at efficient quantity and a pharmaceutically acceptable carrier. Method for preventing and treating chronic fatigue syndrome should be fulfilled due to introducing the mentioned pharmaceutical composition at its daily dosage of 250-1500 mg for 5-20 d to provide the chance for repeating the course of therapy after an interval of 5 d or more. While treating chronic fatigue syndrome one should additionally apply cavinton, adenosine triphosphate, vitamins, cibazone, mesapam to realize the mentioned indication.

EFFECT: higher efficiency.

4 cl, 6 ex, 4 tbl

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