1-[w-(n,n-substituted amino) alkyl]-2-(2*991-allatini) pyrrole or their pharmaceutically acceptable salts, possessing antiarrhythmic and antiischemic activity

 

(57) Abstract:

The invention relates to the field of chemistry of biologically active substances, which may have application in medicine. The proposed biologically active compounds belong to a new group of 1,2-substituted pyrrole General formula

< / BR>
The claimed compounds in the experiment have a pronounced antiarrhythmic and antiischemic activity and intensity and duration of the effect surpass applied in the clinic selected as a prototype reference antagonists Ca++- verapamil and diltiazem. 14 table.

The invention relates to the field of chemistry of biologically active compounds, specifically to a new group of 1,2-substituted pyrrol-1-[w-(N,N-substituted amino)alkyl] -2-(21-acyl-ethinyl)pyrrole and their pharmaceutically acceptable salts, possessing antiarrhythmic and antiischemic activity, the General formula

(I)

where n is 2 or 3, R C1-C2-alkyl or RR together with the nitrogen atom represent a residue of a saturated heterocycle, R1-Me, an aryl.

The above compound (I), their properties and the method of obtaining not described in literature.

The closest prototype of the chemical structure allaih pharmacological properties. So, they have analgesic, antihistaminic and local anesthetic effect. The prototype for this series of compounds for pharmacological activity was selected antagonist ions Ca++verapamil, which, as you know, has a pronounced antiarrhythmic and antiischemic properties [2] moreover, according to preliminary data, the claimed compounds have the ability to block the slow Ca++channels, i.e., have the properties of antagonists of Ca++.

The inventive compounds of General formula (I) showed a pronounced antiarrhythmic effect in chloralkali, aconitine, strofantino intoxication and Harris model with two-stage ligation of the coronary artery. In addition, the inventive compounds discovered the ability to protect the heart from acute ischemic injury.

Compounds of General formula (I) have low toxicity, high therapeutic breadth, well tolerated by the animals in the experiment. These pharmacological and Toxicological results allow us to apply the compounds for the treatment of arrhythmias.

The purpose of the invention synthesis of new derivatives of pyrrole General formula (I) with protivogazy of these compounds to block the slow Ca++channels, i.e., to reveal the properties of antagonists of Ca++.

1-[w-(N, N-substituted amino)alkyl] -2-(21-allatini)pyrrole I get condensation in absolute ethyl alcohol corresponding 1-substituted pyrrolopyridine III with the corresponding ketone IV according to the following scheme:

< / BR>
where II1-10.

II-1 n=2, R=C2H5, R1=Ph; HX=HOOCCH2C(OH)COOHCH2COOH;

II-2 n=3, R=CH3, R1=Ph; HX=HOOCCH2(OH)COOHCH2COOH;

II-3 n=3, R=C2H6, R1=CH3; HX=HOOCCH2(OH)COOCH2COOH;

II-4 n=3, R=C2H5, R1=Ph; HX=HOOCCH2(OH)COOHCH2COOH;

II-5 n=3, R=C2H5, R1=4-BrC6H4; HX=HOOCCH2(OH)COOHCH2COOH;

II-6 n=3, R=C2H5, R1=4-ClC6H4; HX=HOOCCH2(OH)COOHCH2COOH;

II-7 n=3, R=C2H5, R1=4-MeOC6H4; HX=HOOCCH2COOH;

II-8 n=3, R=C2H5, HX=HOOCCH2(OH)COOHCH2COOH;

II-9 n=3, R=C2H5, HX=COOHCOOH;

II-10 n=3, R1=Ph; HX=COOHCOOH.

The condensation is carried out in the environment methyl or ethyl alcohols in the presence of the corresponding sodium alcoholate at room temperature. Then the reaction mass is treated with water, the products of con-10) is a viscous, high-boiling oil, insoluble in water and soluble in organic solvents. Some of the obtained compounds crystallizes upon standing.

Salt acid accession (II, 1-10) are obtained by the interaction of alcohol solutions of the corresponding bases (I, 1-10) and related organic acids. Salts were obtained with oxalic and citric acids. Salt (II, 1-10) are crystalline substances pale yellow, soluble in water, aqueous alcohol, insoluble in ether, benzene.

The structure of the synthesized compounds I, II, confirmed by the results of elemental analysis and spectral data. So, in the PMR spectrum of compound 1-4 have multiplet 5,3-H protons ( 6,6-6,8 m.q) and a doublet of doublets 4-H proton (6.1 m.q) pyrrole cycle. The protons of phenyl radical form multiplet (d 7,2 7,4 m.q) for the para - and meta-protons and a multiplet (d 7,9 8,0 m. q) for ortho-protons. The protons of the two methyl groups and the methylene protons at C11give the triplets, respectively, while (d 0,9 m.q) and (d 4,1 m.q). The three protons of methylene groups on the nitrogen atom form a multiplet (d 2,1 2,6 m.q). Centered multiplet at d 1.8 m.q) corresponds to the methylene protons at C-21. The protons at carbon double links give two do what somename or to be a mixture of spatial isomers. From the data of the PMR spectra, it follows that the constant of spin-spin interaction of protons with carbon double connection is 16 Hz and there is no constant vicinal interaction of protons 9 Hz. From these results it follows that the compounds I and II are TRANS-isomers.

Experimental chemical part

Example 1. 1-[21(diethylamino)ethyl]-2-(31-oxoprop-1-yl)pyrrole (I-1)

To a solution of 1.36 g (0.02 mol) of ateleta sodium in 10 ml of abs.ethanol is added at a temperature of 10 15oC solution of 2.64 (0,022 mol) of acetophenone in 10 ml of abs. ethanol and a solution of 3.88 g (0.02 mol) of 1-[21(diethylamino)ethyl]pyrrole-2-aldehyde (III-I) in 10 ml of abs.of ethanol. The reaction mass is left for 3 days. treated with 50 ml of water and extracted with benzene (3x30 ml). The benzene is evaporated, the residue is distilled in vacuum, collecting the fraction with so Kip. 208 210oC at 1 mm RT. senior Get of 3.73 g (63%) I-1.

Found, C 76,97; H 8,19; N 8,97; C19H24N2O.

Calculated C 76,99; H 8,16; N 9,45.

HYDROCITRIC II-1

To a solution 2,31 g (to 0.011 mol) of citric acid in 10 ml of ethanol was added 2,96 g (0.01 mol) of I-1 in 5 ml of ethanol. The precipitation is filtered off, recrystallized from ethanol, so pl. 89 90oC. Get 2,88 g (57%) II-1.

Example 2. 1-[31-(dimethylamino)propyl] -2-(31-phenyl-31-oxoprop-1-yl)pyrrole (I-2).

To a solution of 1.36 g (0.02 mol) of ateleta sodium in 10 ml of abs. ethanol is added at a temperature of 10 15oC a solution of 2.64 g (0.22 mol) of acetophenone in 10 ml of abs. ethanol and a solution of 3.6 g (0.02 mol) of 1-[33-(dimethylamino)propyl]pyrrole-2-aldehyde (III-2) in 10 ml of abs. of ethanol. The reaction mass leave on for 6 days. treated with 50 ml of water and extracted with 3x30 ml of benzene. The benzene is evaporated, the residue is distilled in vacuum, collecting the fraction with so Kip. 215 216oC at 2 mm RT.article Obtain 4.5 g (58,5%) I-2.

Found, C 76,97; H 7,65; N 9,82; C18H22N22O.

Calculated C 76,56; H A 7.85; N 9,92.

HYDROCITRIC II-2

To a solution 2,31 g (to 0.011 mol) of citric acid in 10 ml of ethanol was added 2,82 g (0.01 mol) of I-2 in 5 ml of ethanol. The precipitation is filtered off, recrystallized from ethanol. Get 2.66 g (54%) II-2, so pl. 104-106oC.

Found, C 60,62; H 6,35; N 6,20; C18H22N2O C6H8O7.

Calculated C 60,75; H 6,37; N 5,9.

Example 3. 1-[31(diethylamino)propyl] -2-(31-methyl-31-oxoprop-1-yl)pyrrole (I-3).

To a solution of 1.36 g (0.02 mol) of ateleta sodium in 10 ml AB g (0.02 mol) of 1-[31(diethylamino)propyl]pyrrole-2-aldehyde (III-3) in 10 ml of abs. of ethanol.

The reaction mass is left for 3 days. treated with 50 ml of water and extracted with benzene (g ml). The benzene is evaporated, the residue is distilled in vacuum, collecting the fraction with so Kip. 181-183oC at 2 mm RT. Art. nd231,5725. Obtain 2.4 g (54%) I-3.

Found, C 72,37; H 9,68; N 11,08; C15H24N2O.

Calculated C 72,54; h 9,74; N 11,28.

HYDROCYCUT II-3

To a solution 2,31 g (to 0.011 mol) of citric acid in 10 ml of ethanol was added 2,48 g (0.01 mol) of I-3 in 5 ml of ethanol. The precipitation is filtered from ethanol. Get 2,37 g (54%) I-3, so pl. 87-89oC.

Found, C 57,09; H 7,40; N 6,50; C15H24N2O C6H8O7.

Calculated C 57,26; H 7,32; N 6,36.

Example 4. 1-[31(diethylamino)propyl] -2-(31-phenyl-31-oxoprop-1-yl)pyrrole (I-4).

To a solution of 1.36 g (0.02 mol) of ateleta sodium in 10 ml of abs. ethanol is added at a temperature of 10-15oC a solution of 2.64 g (0,022 mol) of acetophenone in 10 ml of abs. ethanol and a solution of 4.16 (0.02 mol) III-3 in 10 ml of abs. of ethanol. The reaction mass is left for 3 days. treated with 50 ml of water and extracted with benzene (g ml). The benzene is evaporated, the residue is distilled in vacuuum and 3.72 g (60%) I-4.

Found, C 77,64; H a 8.34; N 9,00; C20H26N2O.

Calculated C 77,88; H 8,44; N 9,02.

HYDROCYCUT II-4

To a solution 2,31 g (to 0.011 mol) of citric acid in 10 ml of ethanol was added 3.1 g (0.01 mol) of I-4 in 10 ml of ethanol. The precipitation is filtered off, recrystallized from ethanol. Obtain 3.1 g (60%) II-4, so pl. 118-119oC.

Found, C 62,09; H of 6.68; N of 5.83; C20H26N2O C6H8O7.

Calculated C 62,14; H 6,82; N 5,57.

Example 5. 1-[31(diethylamino)propyl] -2-[31-(p-bromophenyl)-31-oxoprop-1-yl]-pyrrole (1-5)

To a solution of 1.36 g (0.02 mol) of ateleta sodium in 10 ml of abs.ethanol is added at a temperature of 10-15oC solution of 4.38 g (0,022 mol) of p-bromination in 10 ml of abs. ethanol and a solution of 4.16 g (0.02 mol) III-3 in 10 ml of abs. of ethanol. The reaction mass is left for 3 days. treated with 50 ml of water and extracted with benzene (g ml). The benzene is evaporated, the residue is distilled in vacuum, collecting the fraction with so Kip. 228-230oC at 1 mm RT.article Get to 4.2 g (54% ) of I-5.

Found, C is 61.3; H 6,32; N 7,1; C20H25N2OBr.

Calculated C Of 61.7; H 6,47; N 7,19.

HYDROCYCUT II-5

To a solution 2,31 g (to 0.011 mol) of citric acid in 10 ml of ethanol was added to 3.89 g (0.01 mol) of I-5 in 10 ml of ethanol>/BR>Found, C 53,58; H 5,67; N to 4.52; C20H25N2OBr C6H8O7.

Calculated C 53,71; H 5,72; N 4,82.

Example 6. 1-[31(diethylamino)propyl] -2-[31-(p-chlorophenyl)-31-oxoprop-1-yl]-pyrrole (I-6)

To a solution of 1.36 g (0.02 mol) of ateleta sodium in 10 ml of abs.ethanol is added at a temperature of 10-15oC solution 3,39 g (0,022 mol) of p-chloracetate in 10 ml of abs.ethanol and a solution of 4.16 g (0.02 mol) III-3 in 10 ml of abs.of ethanol. The reaction mass is left for 3 days. treated with 50 ml of water and extracted with benzene (g ml). The benzene is evaporated, the residue is distilled in vacuum, collecting the fraction with so Kip. 240-242oC at 2 mm RT.article Get of 3.56 g (52%) I-6.

Found, C 69,32; H 7,15; N 8,05; C20H25N2OCl.

Calculated C 69,65; H 7,31; N 8,12.

HYDROCYCUT II-6

To a solution 2,31 g (to 0.011 mol) of citric acid in 10 ml of ethanol was added to 3.45 g (0.01 mol) I-6 in 10 ml of ethanol. The precipitation is filtered off, recrystallized from ethanol. Obtain 3.0 g (5,55%) II-6, so pl. 122-123oC.

Found, C 57,95; H 5,97; N equal to 4.97; C20H25N2OCl C6H8O7.

Calculated C 58,15; H Is 6.19; N 5,22.

Example 7. 1-[31(diethylamino)propyl] -2-[31-(p-methoxyphenyl)-31-oxoprop-1UP>oC solution of 3.3 g (0,022 mol) of p-methoxyacetophenone in 10 ml of abs.ethanol and a solution of 4.16 g (0.02 mol) III-3 in 10 ml of abs. of ethanol. The reaction mass is left for 3 days. treated with 50 ml of water and extracted with benzene (g ml). The benzene is evaporated, the residue is distilled in vacuum, collecting the fraction with so Kip. 232-233oC at 1 mm RT.article Get of 3.54 g (52%) I-7.

Found, C 73,88; H 8,11; N 8,11; C21H28N2O2.

Calculated C 74,08; H 8,29; N 8,23.

HYDROCYCUT II-7

To a solution 2,31 g (to 0.011 mol) of citric acid in 10 ml of ethanol was added 3.4 g (0.01 mol) I-7 in 10 ml of ethanol. The precipitation is filtered off, recrystallized from ethanol. Obtain 2.9 g (54%) II-7, so pl. 109-110oC.

Found, C 60,48; H 6,62; N of 5.29; C21H28N2O2C6H8O7.

Calculated C 60,89; H For 6.81; N 5,26.

Example 8. 1-[31(diethylamino)propyl]-2-(31-thienyl-31-oxoprop-1-yl)-pyrrole (I-8)

To a solution of 1.36 g (0.02 mol) of ateleta sodium in 10 ml of abs.ethanol is added at a temperature of 10-15oC solution 2,77 g (0,022 mol) of 2 - acetylthiophene in 10 ml of abs.ethanol and a solution of 4.16 g (0.02 mol) III-3 in 10 ml of abs.of ethanol. The reaction mass is left for 3 days. treated with 50 ml of water and extracted with benzene (g ml). Benzene was allsouls, so pl. 52-4oC. Obtain 3.6 g (57%) of I-8.

Found, C 68,11; H 7,45; N 8,71; C18H24N2OS.

Calculated C 68,31; H Of 7.64; N Cent To 8.85.

HYDROCITRIC II-8

To a solution 2,31 g (to 0.011 mol) of citric acid in 10 ml of ethanol was added, and 3.16 g (0.01 mol) of I-8 in 10 ml of ethanol. The precipitation is filtered off, recrystallized from ethanol. Obtain 3.2 g (63%) II-8, so pl. 80 81oC.

Found, C 56,53; N 6,30; N 5,85; C18H24N2OS C6H8O7.

Calculated C 56,68; H 6,34; N 5,51.

Example 9. Hydrocalc 1-[31(diethylamino)propyl] -2-(31-intracel-31-oxoprop-1-yl)-pyrrole (I-9)

To a solution of 1.36 g (0.02 mol) of sodium methylate in 10 ml of abs.methanol was added to the solution to 4.62 g (0,021 mol) 10-acetylanthracene in 40 ml of abs. methanol and a solution of 4.16 g (0.02 mol) III-3 in 10 ml of abs.of methanol. The reaction mass is left for 3 days. treated with 50 ml of water and extracted with benzene (3x30 ml). The benzene is evaporated, the residue is crystallized from ethanol, so pl. 72 73oC. Obtain 4.35 g (53%) I-9.

Found, C 81,97; H 7,24; N 6,76; C28H30N2O.

Calculated C 81,91; N. Of 7.36; N 6,82.

OXALATE II-9

To a solution of 1.39 g (to 0.011 mol) of oxalic acid in 20 ml of ethanol is added a solution of 4.1 g (0.01 mol) I-9183 184oC.

Found, C 71,68; H 6,79; N 5,46; C28H30N2O C2H2O4.

Calculated C 71,98; H 6,44; N 5,6.

Example 10. 1-[31-(morpholyl)propyl] -2-(31-phenyl-31-oxoprop-1-yl)-pyrrole (I-10)

To a solution of 1.36 g (0.02 mol) of ateleta sodium in 10 ml of abs. ethanol is added at a temperature of 10 15oC a solution of 2.64 g (0,022 mol) of acetophenone in 10 ml of abs.ethanol and a solution of 4.44 g (0.02 mol) of 1-[31-(morpholyl)propyl]pyrrole-2-aldehyde (III-4) in 10 ml of abs. of ethanol. The reaction mass is left for 3 days. treated with 50 ml of water and extracted with benzene (3x30 ml). The benzene is evaporated, the residue is distilled in vacuum, collecting the fraction with so Kip. 260 262oC at 1 mm RT.article Get of 3.69 g (57%) of I-10.

Found, C 73,88; H of 7.23; N 8,45; C20H24N2O2.

Calculated C 74,04; N 7,46; N 8,63.

OXALATE II-10

To a solution of 1.39 g (to 0.011 mol) of oxalic acid in 20 ml of ethanol is added a solution 3,24 g (0.01 mol) of I in 15 ml of ether. The precipitation is filtered off, recrystallized from ethanol. Get 2,19 g (57%) II-10.

Found, C 63,55; H 6,17; N 6,68; C2OH24N2O2C2H2O4.

Calculated C 63,75; H 6,3; N 6,77.

Pharmacological part

Example 1. [3] in experiments on outbred adult white mice of both sexes weighing 18 to 20 g

The results are shown in table. 1.

Example 2. A comparative study of the antiarrhythmic activity of the claimed compounds and prototypes to model chloralkali fibrillation

Chloralkali arrhythmia caused intravenous 10% solution of calcium chloride at a dose of 250 mg/kg and above. Arrhythmia develops within 3 to 5 minutes and is largely a function disorders of excitability and conductivity, or both functions simultaneously. First picked up a dose of calcium chloride, causing lethal ventricular fibrillation, then the compounds were administered intravenously for 1 min before the introduction of prescribed lethal doses of calcium chloride.

Evaluation of the antiarrhythmic action of the compounds was performed to reduce the incidence of lethal ventricular fibrillation.

The results of the experiments are presented in table. 2. As Comparators used verapamil and diltiazem.

As can be seen from the table. 2, all of the claimed compounds in this model exhibit antiarrhythmic activity, and compounds 1-4, 1-3 and 1-8 in its antiarrhythmic activity exceed prototypes.

Example 3. A comparative study of the effect of the claimed compounds and ucal, 40 mg/kg body weight of the animals, in/in) weight 2,7 3,0 kg Threshold electrical ventricular fibrillation of the heart was determined by repeating the scanning electrically vulnerable period of the cardiac cycle (the rising part of the wave T ECG) in a series of 20 square wave DC increasing intensity (pulse duration of 4 MS, a frequency of 50 pulses/s) prior to the occurrence of atrial fibrillation. The threshold value of AF was evaluated by the minimum intensity of the current (in milliamperes), causing fibrillation. The compounds were injected for 5 min prior to stimulation (table. 3).

It follows from the presented results, all of the claimed compounds in varying degrees, are antifibrillatory activity. The most effective on this model proved to be compounds 1-4, 1-7 and 1-9.

Example 4. Comparative study of anti-arrhythmic properties of the claimed compounds in comparison with the prototype model Harris

In dogs the day before the start of the experiment was ligated bending branch of the left coronary artery 3 to 5 mm below the exit from under the eye. According to the model [4] and our own observations after 24 h in dogs, operated thereby, develops persistent polytopia left ventricular e is alnost and the intensity of the effect.

The results obtained are presented in table. 4.

Obtained in this series of experiments suggests that in this model, the pathology of the greatest efficiency shows the connection 1-4, which according to the intensity and duration of the effect is considerably larger than the prototype. However, it should be emphasized that all of the claimed compounds to some extent on the model of Harris exhibit antiarrhythmic activity.

Example 5. Study of the effect of the inventive compounds on basic hemodynamics and heart have shot animals with acute myocardial ischemia

The experiments were carried out on outbred adult cats of both sexes weighing 2.5 to 3.5 kg, shot with Nembutal (40 mg/kg, in/in). Animals were placed on artificial respiration oxygen-air mixture under the control of the blood (pH 7,35 7,45; pO2above 90 mm RT.cent.). The body temperature of the animal was maintained at a constant level.

Was catheterizable the femoral vein for administration of the compounds and the femoral artery for measurement of systemic blood pressure, as well as for sampling blood gas analysis.

On the ascending part of the aorta arch implanted sensor is or catheter for registration of left ventricular pressure and its first and second derivatives.

During the whole experiment was recorded ECG in II standard lead.

Based on the analysis of the recorded curves (curves phase of blood flow in the ascending part of the aorta arch, arterial and left ventricular pressure; ECG) has identified the following hemodynamic parameters and cardiac activity: mean arterial pressure (SBP), heart rate (HR); shock and minute volume of the heart; the index of energy expenditure and heart; airway diseases.

The compounds were administered at a constant speed and at constant volume. Compounds were dissolved in physiological solution. In a control series of experiments, animals were injected with the same volume of solvent.

Acute myocardial ischemia caused by simultaneous ligation of the descending branch of the left coronary artery on the border of the middle and lower third.

In the control series of experiments (table.5) 60-minute myocardial ischemia leads to a significant violations by the heart function and hemodynamics.

Data on the effect of some of the claimed compounds and the comparison drug verapamil on the main hemodynamic parameters and cardiac activity in terms of overall ISO, that the claimed compounds in acute myocardial ischemia to a certain extent, prevent the development of gross misconduct hemodynamics and heart activity. The greatest effect on this model showed the connection 1 4, which in its activity is not inferior to the prototype.

Example 6. Study of the effect of the inventive compounds on intracardiac hemodynamics in shot cats with acute myocardial ischemia

The shot of the cats who have acute myocardial ischemia was caused by simultaneous ligation of the descending branch of the left coronary artery on the border of the middle and lower thirds, using M-echocardiography were evaluated:

1. Dsanterior-posterior dimensions of the left ventricle in systole;

2. Bbanterior-posterior dimensions of the left ventricle in diastole;

3. LEVT time reduction of the rear wall;

4. Vsvolume of the left ventricle in systole;

5. Vdvolume of the left ventricle in diastole;

6. Svstroke volume of the heart;

7. Cothe minute volume of blood;

8. Vcfthe circulatory speed of shortening of the myocardium;

9. HR, heart rate;

10. EF ejection fraction;

11. DS is the degree of shortening of the anterior-posterior size of the left LASS="ptx2">

As can be seen from the table. 10, a three-hour ischemia of the myocardium leads to gross violations by intracardiac hemodynamics.

The claimed compounds (table. 11) significantly inhibit the development of intracardiac hemodynamics and maintain the pumping function of the heart at an adequate level.

The results obtained in this series of experiments, the data correlate well with the results given in the previous example, and allow us to conclude that the claimed compounds have anti-ischemic properties.

Example 7. The study of anti-ischemic properties of the inventive compounds on the ultrastructural level

In experiments on shot cats ischemia of the myocardium caused by simultaneous ligation of the descending branch of the left coronary artery on the border of the middle and lower thirds. After 3 h from the start of ischemia, animals were scored, and the myocardium of the left ventricle were taken for ultrastructural studies.

For this purpose, pieces of the heart muscle in experimental animals subendocardialnah areas and from the depth of the myocardium in ischemic and nisemididoronokai zones were fixed in 3.5% solution of glutaric aldehyde 0.2 M cacodylate same buffer with the addition of the tracer, and after dehydration in alcohols of increasing concentration were concluded in the mixture Epona and Araldite.

As shown by electron microscopic analysis of the control series, after a three-hour ischemia in ischemic areas of subendocardial detected edema sarcoplasma cardiomyocytes, reducing the number of granules glycogen until the complete elimination of the formation of large vacuoles, occurring from dilational sarcoplasmatic reticulum and died dramatically swollen mitochondria. Especially pronounced was swelling in coladeras sarcoplasma were noted marginalia chromatin in the nuclei of cardiomyocytes. Met cardiomyocytes with a relatively intact ultrastructure, slightly enlightened lifebalance sarcoplasma, however, there have been local lysis of myofibrils. Ionic lanthanum could be seen as on the border of cardiomyocytes, and within their sarcoplasma, as well as in mitochondria irreversibly modified cardiomyocytes.

In animals, which after 60 min from the start of ischemia was introduced intravenously connection 1 4 (fence material produced as in the control series: after 3 h from the start of ischemia in ischemic cardiomyocytes subangular iunie number of cythrawl glycogen identified individual lipid inclusions, complementary mechanism, small vacuoles derived from deprived Krist mitochondria, however, most of the mitochondria were intact structure. Through the ischemic subendocardial lanthanum ion does not penetrate through the sarcolemma of cardiomyocytes, he accumulated at the border of the cells, as was also observed in subsarcolemmal vesicles.

The results indicate a pronounced anti-ischemic action of the claimed compounds.

Example 8. Study of the effect of the claimed compounds in comparison with the prototype of the dihydropyridine receptor blockers entrance of Ca++in embryonic fibroblasts

It is known that embryonic fibroblasts contain L-voltage gated calcium channels selectively blocking dihydropyridine antagonists ions Ca++(these include: fenilalkilaminov verapamil; dibenzazepine diltiazem and 4-aryl-1,4-dihydropyridines nifedipine, nitrendipine) [5]

Dihydropyridine blockers are the most selective and highly effective inhibitors of the entry of Ca++. Moreover, the affinity constants of these compounds to the binding sites in the composition of the calcium channel finding is the cue or the effects of these compounds on other regulatory system cells: calmodulin [7] fosfodiesterazu [8] ATP [9] and other Therefore, it is considered that there is a direct relationship between the dihydropyridine receptor blockers and calcium channel L-type in the plasma membrane of cells, for which the characteristic is the presence of a single class of noninteracting binding sites dihydropyridine calcium antagonists. The validity of this conclusion is directly supported by data about the identity full of calcium channels in artificial membranes containing reconstructed purified dihydropyridine receptor blockers [10]

In addition, it is known that fibroblasts of the human embryo is placed in a collagen gel, cause its contraction [11] which is based on the increase in the concentration in the cytoplasm of free ions of Ca++[12] regulation of content through dihydro-pyridine-dependent Ca++channels fibroblasts (channels L-type) [13]

In this work, we used fibroblasts of the human embryo, the preparation of the collagen gel and the measured concentrations were produced according to standard methods [14]

Research shows (table. 12) that the claimed compounds, as well as prototypes, block calcium-dependent L-channels embryonic fibroblast the connections on transmembrane ionic currents through the membrane of cardiomyocytes

In the previous example it was shown that the ability of some of the inventive compounds to inhibit contraction of the gel embryonic fibroblasts that allows you to offer a suggestion about the possibility of a blockade under the influence of these compounds voltage gated Ca++the channels. However, for a more definite answer to this question was necessary to directly assess the effect of the inventive compounds on the magnitude of the transmembrane ion currents.

The experiments were conducted according to the standard method described in [16]

In experiments with fixing the potential on the drug atrial trabeculae frogs placed in the double sucrose bridge, it is shown that the perfusion trabeculae standard ringer's solution containing compound 1-4 at a concentration of 10 mm, was observed a decrease in the total incoming current for all values of membrane potential (table. 13).

Thus, when the value of the depolarization of the membrane potential of 40 mV, which is the maximum value of the incoming current, equal to 1.56 MCA, oppression is 68% With a further increase in the magnitude of the depolarizing the membrane potential up to 50 and 60 mV enhanced dampening inane 1-4 on the magnitude of the slow incoming Ca++current in cases where fast incoming Na+the current was eliminated by replacing the solution NaSl equivalent amount of holdingarea shown that the connection 1-4 completely blocked slow incoming Ca++current at any values of depolarizing membrane potential (table. 14).

When studying the effect of compounds 1-4 (10 nm) on a fast incoming Na+current shows that it is to a certain extent prevents the stimulatory effect of PGL2-Na on membrane currents (formerly K. by Kelemen et al. it is shown that prostacyclin (PGL2-Na) in ascallaway environment increases fast incoming Na+the current through the membrane of cardiomyocytes [15]

Thus, according to the data obtained from the study of the effect of the inventive compounds on the magnitude of the transmembrane ion currents shows that the connection 1-4 completely ceases slow incoming Ca++and to a certain extent reduces the fast incoming Na+the currents through the membrane of cardiomyocytes.

When comparing our findings regarding the effect of the inventive compounds on the magnitude of the slow incoming Ca++current through the membrane of cardiomyocytes with the materials known from the literature [17, 18] it should be noted, C exceeds prototypes verapamil and diltiazem.

Thus, according to the data of pharmacological studies above, the inventive compounds have a pronounced antiarrhythmic and antiischemic activity and in some cases greatly exceed in intensity steps prototypes verapamil and diltiazem.

Based on our data, one can make the assumption that the decisive role in the implementation of antiarrhythmic and antiischemic effects of the inventive compounds plays their ability to block the slow Ca++the channels of the membrane of cardiomyocytes, i.e., the claimed compounds exhibit properties inherent antagonists Ca++.

1-[-(N,N-substituted amino)alkyl]-2-(21-allatini) pyrrole General formula

< / BR>
where 1-1 n 2, R C2H5, R1Ph;

1-2 n 3, R CH3, R1Ph;

1-3 n 3 R C2H5, R1CH3;

1-4 n 3, R C2H5, R1Ph;

1-5 n 3, R C2H5, R1p-BrC6H4;

1-6 n 3, R C2H5, R1p-ClC6H4;

1-7 n 3, R C2H5, R1p-MeOC6H4;

1-8 n 3, R C2H5,

1-9 n 3, R C2H5,

1-10 n 3, R1Ph,

and their pharmaceutically acceptable the

 

Same patents:

The invention relates to new, therapeutically valuable derivative tetrazole, method of their production and their use

The invention relates to a new alkylenediamine derivative, a method for obtaining and drug treatment for dysuria containing the specified new alkylenediamine derivative or its pharmaceutically acceptable salt as an active ingredient

The invention relates to new oxazolidone derivative having the formula:

to their pharmaceutically acceptable additive salts, and stereochemical isomeric forms, where a1AND2AND3AND4is a bivalent radical having the formula

-CH CH-CH CH- (a-1),

-N CH-CH CH- (a-2)

-CH N-CH CH- (a-3)

-CH CH-N CH- (a-4),

-CH CH-CH N- (a-5),

-N CH-N CH- (a-6) or

-CH N-CH N- (a-7), where one or two hydrogen atoms in said radicals (a-1) to(a-7) can be independently substituted by a halogen atom, a C1-C6-alkyl, C1-C6-alkyloxy, hydroxy, or trifluoromethyl; R represents hydrogen or C1-C4-alkyl; R1represents hydrogen, C1-C6-alkyl or hydroxy WITH1-C6-alkyl;

m is 1 or 2;

represents a C1-C4-alcander; B is an R2CH2, O, SO or SO2where R2is hydrogen or C1-4-alkyl;

n is 0, 1 or 2;

L represents hydrogen; C1-2-alkyl; C3-6-cycloalkyl; C3-C6alkenyl, optionally substituted by aryl; C1-C6-alkylsulphonyl; C1-C6-алкилоксикBR>
-Alк-Y-R4(o-2);

-Alк-Z1-C X-2-R5(o-3); or

-CH2-CHOH-CH2-O-R6(o-4); where R3represents cyano, aryl or Het; R4represents hydrogen, aryl, Het, or1-C6-alkyl, optionally substituted aryl or Het; R5represents hydrogen, aryl, Het or1-C6-alkyl, optionally substituted aryl or Het; R6represents aryl or naphthalenyl; Y represents O, S, NR7where R7is hydrogen, C1-C6-alkyl or C1-C6-alkylcarboxylic;

Z1and Z2each independently represents O, S, NR8or a simple link, where R8is hydrogen or C1-C6-alkyl; X represents O, S or NR9where R9is hydrogen, C1-C6-alkyl or cyano; Alк each independently is a C1-C6-Alcantara; each Het represents: (i) optionally substituted heterocyclic ring with 5 or 6 members containing 1, 2, 3 or 4 heteroatoms selected from oxygen, sulfur and nitrogen, provided that there is not more than 2 oxygen atoms and/or sulfur; (ii) optionally substituted heterocyclic ring with 5 or 6 members which of substituted five - or six-membered ring through 2 carbon atoms or 1 nitrogen atom; and that in the rest of the condensed ring contains only carbon atoms; (iii) optionally substituted heterocyclic ring with 5 or 6 members, which contains 1 or 2 heteroatoms selected from oxygen atoms, sulfur and nitrogen, and optionally substituted five - or six-membered ring through 2 carbon atoms or 1 carbon atoms and 1 nitrogen atom; and which in the rest of the condensed ring contains 1 or 2 heteroatoms selected from oxygen atoms, sulfur and nitrogen; and, if Het is a monocyclic ring system, it is not necessary to have up to 4 substituents; and if Het is a bicyclic ring system, it may not necessarily be up to 6 substituents, which are selected from halogen, amino, mono - and di(C1-C6-alkyl)amino, aryl WITH1-C6-amino, nitro, cyano, aminocarbonyl,1-C6-alkyl, C1-C6alkyloxy,1-C6-alkylthio,1-C6-allyloxycarbonyl,1-6-alkyloxy-FROM1-6-alkyl, C1-6-allyloxycarbonyl1-6-alkyl, hydroxy, mercapto, hydroxy1-C6-alkyl, C1-C6-alkylcarboxylic aryl, Rilc1-C6-alkylamino is whether 3 substituents, each of which is independently selected from halogen, hydroxy, nitro, cyano, trifloromethyl,1-C6-alkyl, C1-C6-alkyloxy,1-C6-alkylthio, mercapto, amino, mono - and di-(C1-C6-alkyl)amino, carboxyl,1-6-allyloxycarbonyl, and C1-C6-alkylcarboxylic

The invention relates to new derivatives of 3(2H)-pyridazinone and to their pharmaceutically acceptable salts, possessing inhibitory activity against the aggregation of platelets, cardiotonic activity, vasodilating activity, anti-SRS-A activity, to processes for their preparation and to pharmaceutical compositions containing them as active ingredient

The invention relates to a compact, crystalline 3-cyan - 2-morpholino-5-(pyrid-4-yl)-pyridine with high apparent (bulk) density and method thereof

The invention relates to new biologically active chemical compounds, namely, to derive a cyclic amide of the formula I

R1-(CH2)n-Z,

where R1group cyclic amide, such as 2H-3,4-dihydro-1,3-benzoxazin-2-she, 2H-3,4-dihydro-1,3-benzoxazin-2,4-dione, and 1,2,3,4-tetrahydroquinazoline-2,4-dione, and 1,2,3,4-tetrahydroquinazolin-2-it, 1,2,3,4-tetrahydropyrido(3,2-d)-pyrimidine-2,4 - dione, and 1,2,3,4-tetrahydropyrido(3,2-d)pyrimidine-2-it, 1,2,3,4-tetrahydropyrimidine-2,4-dione, pyrrolidin-2-it, 1,2,3,4 - tetrahydropyridine-2-it, 5H-6,7,8,9-tetrahydropyrido(3,2-b)azepin-6-she N-5,6,7,8-tetrahydropyrido(2,3-b)azepin - 8-she, 2H-3,4-dihydropyrido(2,3-e)-1, 3-oxazin-2-thione or 2-she pyrrolidine (3,4-b)-pyrazin-5-she 1H-2,3,4,5-tetrahydrothieno(2,3-b)indol-2-it, 8H-4,5,6,7-tetrahydrothieno(2,3-b)thiophene-7-she 4H-pyrazolo(5,4-f)benzazepin-9-it, isoindoline-1,3-dione, benzoxazolyl-2-it, unsubstituted or substituted lower alkyl, lower alkoxy, halogen, the nitro-group, carboxy, benzoyl or benzyl, n is zero or an integer from 1 to 6, Z is a group of formula (A) or (B):

N-(CH2)mR2(A) or -(CH2)p, dioxolane, furan, tetrahydrofuran, methylfuran or thiophene, m is an integer from 1 to 3; R3is lower alkyl; R4is phenyl or a radical of dioxolane, furan or thiophene, p = 1, provided that when R1radical 1,2,3,4-tetrahydrobenzo-2-or 1,2,3,4-tetrahydroquinazoline-2,4-dione, R2and R4are not phenyl or substituted by a halogen phenyl, or their pharmacologically acceptable salts with antiacetylcholinesterase activity

The invention relates to the field of organic chemistry and relates to a method of obtaining new derivatives of imidazole

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: invention relates to 5-membered N-heterocyclic compounds and salts thereof having hypoglycemic and hypolipidemic activity of general formula I , wherein R1 is optionally substituted C1-C8-alkyl, optionally substituted C6-C14-aryl or optionally substituted 5-7-membered heterocyclic group, containing in ring 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; or condensed heterocyclic group obtained by condensation of 5-7-membered monoheterocyclic group with 6-membered ring containing 1-2 nitrogen atoms, benzene ring, or 5-membered ring containing one sulfur atom; { is direct bond or -NR6-, wherein R6 is hydrogen atom or C1-C6-alkyl; m = 0-3, integer; Y is oxygen, -SO-, -SO2- or -NHCO-; A ring is benzene ring, condensed C9-C14-aromatic hydrocarbon ring or 5-6-membered aromatic heterocyclic ring containing 1-3 heteroatoms selected from oxygen and nitrogen, each is optionally substituted with 1-3 substituents selected from C7-C10-aralkyloxy; hydroxyl and C1-C4-alkoxy; n = 1-8, integer; B ring is nitrogen-containing 5-membered heterocycle optionally substituted with C1-C4-alkyl; X1 is bond, oxygen or -O-SO2-; R2 is hydrogen atom, C1-C8-alkyl, C7-C13-aralkyl or C6-C14-aryl or 5-6-membered heterocyclic group containing in ring 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with 1-3 substituents; W is bond, C1-C20-alkylene or C1-C20-alkenylene; R3 is -OR8 (R8 is hydrogen or C1-C4-alkyl) or -NR9R10 (R9 and R10 are independently hydrogen or C1-C4-alkyl). Compounds of present invention are useful in treatment of diabetes mellitus, hyperlipidemia, reduced glucose tolerance, and controlling of retinoid-associated receptor.

EFFECT: new medicines for treatment of diabetes mellitus, hyperlipidemia, etc.

26 cl, 518 ex, 3 tbl

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

SUBSTANCE: invention relates to new derivatives of propene carboxylic acid amidooximes of the formula (I):

wherein R means phenyl that is substituted optionally with 1-3 substitutes wherein substitute means (C1-C2)-alkyl or (C1-C2)-alkoxy-group; R' means hydrogen atom (H); R4 and R5 mean independently of one another H, (C1-C5)-alkyl, phenyl that is substituted optionally with 1-3 substitutes wherein substitute means (C1-C2)-alkyl or (C1-C2)-alkoxy-group; or R4 and R5 in common with adjacent nitrogen atom form 5- or 6-membered saturated or unsaturated heterocyclic group that can comprise additional nitrogen atom or oxygen atom as a heteroatom and it can be condensed with benzene ring, and heterocyclic group and/or benzene ring can comprise one or two substitutes wherein substitute means (C1-C2)-alkyl or (C1-C2)-alkoxy-group; R1 and R2 mean H; R3 means H, OH; or R1 in common with R2 forms carbonyl group wherein carbon atom is joined with oxygen atom adjacent with R1 and with nitrogen atom adjacent with R2; R3 means H, OH; or R2 means H; and R1 in common with R3 form a valence bond between oxygen atom adjacent with R1 and carbon atom adjacent with R3; and its geometric isomers and/or optical isomers, and/or its pharmaceutically acceptable acid-additive salts. Compounds of the formula (I) inhibit activity of poly(adenisone diphosphate ribose) polymerase and can be used in pharmaceutical composition in treatment of states based on inhibition of this enzyme activity, and in treatment of states associated with oxygen insufficiency of heart and brain. Also, invention describes methods for preparing compounds of the formula (I).

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

9 cl, 1 tbl, 41 ex

FIELD: pharmacy, pharmaceutical technology.

SUBSTANCE: invention relates to a novel crystalline form VI of atorvastatin calcium, or its hydrates. Invention proposes a picture of powdery roentgen diffraction with value 2Θ determined by using Shimadzu XRD-6000 with K-radiation of copper at λ = 1.5406 Å and with relative intensity >15%, 3.7365; 7.7200; 8.6985; 10.2185; 12.5933; 17.9103; 18.3600; 19.4031; 20.2800; 20.8200; 22.5122 and 25.5848. Also, invention describes methods for their preparing. Invention provides high purity, stability and solubility of proposed form.

EFFECT: improved and valuable properties of form VI.

22 cl, 2 tbl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel α-(N-sulfonamido)acetamides of the formula (I) or their optical isomers wherein values R1, R, R2 and R3 are given in the invention claim. Proposed compounds are inhibitors of production of β-amyloid peptide and can be used for inhibition of production of β-amyloid peptide. Also, invention relates to pharmaceutical composition based on these compounds and to a method for inhibition of production of β-amyloid peptide.

EFFECT: valuable medicinal property of compounds and pharmaceutical composition.

22 cl, 23 sch, 4 tbl, 501 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel compounds of formula (1) , in form of trans- or cis-isomers, or their mixture, where R1 is selected from , and ; R7 stands for lower alkyl; R8 stands for lower alkyl; X represents >C=O or >SO2; R9 and R11 represent hydrogen or together form double bond; R10 and R12 are independently selected from hydrogen or lower alkyl; m stands for 1 or 2; n stands for 0, 1 or 2 and their pharmaceutically acceptable salts. Invention also relates to pharmaceutical composition and to application of said compounds, as well as compounds of formula (I), where R1 represents (R2, R3, R4, R5 and R6 each is independently selected from hydrogen, lower alkyl, lower alkoxy group or halogen; on condition that R2, R3, R4, R5 and R6 do not represent hydrogen), for treatment and/or prevention of DPP-IV-associated diseases.

EFFECT: obtaining novel compounds for treatment and/or prevention of DPP-IV-associated diseases.

14 cl, 1 tbl, 33 ex

FIELD: chemistry.

SUBSTANCE: in formula (I') , R5 is any group selected from a group comprising C1-C6 alkoxy group, which can be substituted with one group selected from a group of β substitutes, phenyloxy group which can be substituted with one group selected from a group of γ substitutes, C1-C6 halogenalkoxy group and C3-C6 cycloalkyloxy group; R6 is a substitute in a benzene ring which is selected from a group of α substitutes; R7 is a hydrogen atom, C1-C6 halogenalkyl group, C1-C6 hydroxyalkyl group which can be substituted with a hydroxy-protective group, C1-C6 alkyl group which can be substituted with one group selected from a group of β substitutes, or a phenyl group which can be substituted with one hydroxy group; m equals 1; n equals 1 or 2; numbers in each benzene ring denote the number of the position of each substitute; the group of substitutes includes hydroxyl groups, nitro groups, cyano groups, C1-C6 dialkylamino groups, acetamide groups, halogen atoms, C1-C6 alkyl groups, which can be substituted with one group selected from a group of β substitutes, C1-C6 halogen alkyl groups, C3-C10 cycloalkyl groups, 6-member heterocyclic groups with an N atom or O atom as a heteroatom, C3-C6 cycloalkenyl groups, phenyl group which can be substituted with one group selected from a group of γ substitutes, 5-6-member heteroaryl groups with 1-3 N atoms as heteroatoms which can be substituted wit one or more groups selected from a group of γ substitutes, C1-C6 alkoxy groups, C1-C6 halogenalkoxy groups, C3-C10 cycloalkoxy groups, phenyloxy group, C1-C6 alkylthio groups, C1-C6 halogenalkylthio groups, C1-C6 alkylsulphonyl groups and C1-C6 alkylcarbonyl groups; the group of β substitutes includes C1-C6 alkoxycarbonyl groups, C3-C10 cycloalkyl groups which can be substituted with one group selected from a group of γ substitutes, C3-C6 cycloalkenyl groups, C6-C10 aryl groups which can be substituted with one or more groups selected from a group of γ substitutes, 5-6-member heteroaryl groups with one N, O or S heteroatom, 9-member heteroaryl groups with two heteroatoms selected from N and S, C1-C6 alkoxy group and C6-C10 aryloxy group; and the group of γ substitutes include cyano groups, C1-C6 dialkylamino groups, C1-C6 cyclic amino groups, halogen atoms, C1-C6 alkyl groups, C3-C10 cycloalkyl grous, C1-C6 halogenalkyl groups, C1-C6 alkoxy groups and C1-C6 alkylenedioxy groups. The invention also relates to compounds or pharmaceutically acceptable salts thereof, selected from: 4-(2-cyclopropylethoxy)-N-(2-(4-ethoxyphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide, 4-(2-cyclopropylethoxy)-N-(2-[4-(cyclopropyloxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide, 4-(2-cyclopropylethoxy)-N-(2-[4-(difluoromethoxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}-vinyl)-benzamide. Other compounds are given in the formula of invention. The invention also relates to a pharmaceutical composition which can inhibit bone resorption, which contains the disclosed compound, to use of the disclosed compound as a medicinal agent for inhibiting bone resorption, for preparing a medicinal agent for lowering concentration of calcium in the blood, for preparing a medicinal agent for inhibiting reduction of bone mass, to a medicinal agent for inhibiting bone resorption in form of the disclosed compound, to a method of inhibiting bone resorption, a method of lowering concentration of calcium in the blood, a method of inhibiting reduction of bond mass, involving addition of an effective amount of the disclosed compound.

EFFECT: more effective use of the compounds.

22 cl, 6 tbl, 116 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (II-A) or pharmaceutically acceptable salt thereof: [in which symbols denote the following: R10-R12: are identical or different and each denotes halogen, lower alkyl, halogen-lower alkyl, -OR0, -O-halogen-lower alkyl or -CN, R13: R0, halogen, halogen-lower alkyl, -OR0, -O-halogen-lower alkyl or -CN, ring B: benzene ring or a 5-6-member heteroaromatic ring containing 1-2 heteroatoms selected from O, S and N, R14: R0, halogen or -OR0, R0: are identical or different and each denotes H or lower alkyl, Y1: a single bond, lower alkylene, lower alkenylene or O-lower alkylene-, and Z1: -CO2R0 or -C0-NH-SO2-lower alkyl]. The invention also relates to a pharmaceutical composition based on the said compound, having antagonistic effect on the EP1 receptor.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in a medicinal agent for treating lower urinary tract symptoms.

6 cl, 56 tbl, 231 ex

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