Gamma-hydroxypropylammonium-5-hydroxynicotinate eliciting anti-ischemic, anti-arrhythmic and hypolipidemic activity
FIELD: organic chemistry, chemical technology, medicine.
SUBSTANCE: invention relates to synthesis of new biologically active substance, namely, to γ-hydroxypropylammonium-5-hydroxynicotinate of the formula (I): , eliciting an anti-ischemic, anti-arrhythmic and hypolipidemic activity. This compound shows low toxicity and absence of cardiodepressive effect. Compound of the formula (I) is prepared by interaction of 5-hydroxynicotinic acid with 3-amino-1-propanol in the presence of a solvent at heating.
EFFECT: valuable medicinal properties of compound.
1 cl, 7 tbl, 3 ex
The invention relates to medicine, specifically to new chemical compound, a derivative of 5-hydroxy-nicotinic acid, which has anti-ischemic, anti-arrhythmic and hypolipidemic activity.
These properties suggest the possibility of using the compounds for the prevention and treatment of coronary heart disease.
Known anti-ischemic and anti-arrhythmic agent from the group β-blockers inderal (Medmaravis. Medicines, M, “Medicine”, 1993, part 1, page 330) has cardiodepressive action does not have hypolipidemic properties and has a relatively high toxicity.
The purpose of the invention is a new compound which has a combined anti-ischemic, anti-arrhythmic and hypolipidemic properties, low toxicity and lack cardiodepressive action.
This goal is achieved by the new connection, and it γ-hydroxypropylamino-5-hydroxynicotinate formula I:
obtained in a known manner: the interaction of 5-hydroxynicotinic acid with 3-amino-1-propanol in the presence of a solvent under heating.
Example 1. γ-Hydroxypropylamino-5-hydroxynicotinate (I).
To a solution of 9.0 g (0.12 moles) of 3-amino-1-propanol in 180 ml of alcohol, add p and stirring 16,68 g (0.12 moles) of 5-hydroxynicotinic acid. The reaction mixture is heated at 75-80°C for 5-7 minutes under reflux, filtered, the filtrate is cooled to 5-7°C. the Formed precipitate was separated, washed with 25 ml of chilled ethanol, dried, get 21,85 g of compound I (yield of 85.1%) of white crystalline product, so pl. 137-137,5°C.
Found, %: 50,51; N To 6.67; N to 13.09: C9H14N2O4.
Calculated. %: 50,47; N IS 6.54; N 13,08.
The infrared spectrum, cm-1: 3180, 3025, 1600, 1570. 1300, 1150, 1050.
Example 2. Determination of acute toxicity of the compounds I.
Acute toxicity of compound I studied in experiments on white mice weighing 18-20 g with the definition of LD50according to the method of Litchfield and Wilcoxon signed intraperitoneal injection. Observation of animals was performed within 48 hours after administration of the substance. The results showed that LD50the compounds I for mice with intraperitoneal injection is more than 5000 mg/kg
Example 3. The study of the cardioprotective action of the compounds I.
3.1. Anti-ischemic activity of the compounds I.
3.1.1. The effect of compound I on the threshold of myocardial ischemia in awake rabbits.
Experiments put on rabbits of the Chinchilla breed weight 5-5,5 kg with pre-implanted in the coronary artery by occluder (Uberzone, Tvironova. Bulletin of experimental biology and medicine, 1984, No. 10, pages 460-462). Test the connection I and the comparison drug inderal was administered intravenously immediately after the establishment of stable threshold myocardial ischemia.
The connection I in the dose range of 0.2 to 5.0 mg/kg povyshalo threshold myocardial ischemia in awake rabbits with effect duration 30-40 minutes (table. 1). The expression of the preventive anti-ischemic effect the connection I was not inferior to the comparator drug inderal taken in effective dose (1 mg/kg).
3.1.2. The effect of compound I on the size of the ischemia and necrosis in acute myocardial ischemia.
Experiments put on nonlinear rats male weighing 250-500 g, anesthetized with atenalol sodium (40 mg/kg intraperitoneally). In animals, translated into controlled breath, simulated myocardial infarction by ligation of the descending branch of the left coronary artery at the level of the lower edge of the atrial appendage. The size of the zone of necrosis and ischemia was determined 4 hours after occlusion of a coronary artery differential display method, the principle of which is based on the separate quantification of Evans blue (indicator of ischemia) and red formazan (indicator necrosis).
As follows from the data presented in table. 2, the connection I in the dose range from 5.0 to 100.0 mg/kg reduces the size of the zone of necrosis after 4 hours after occlusion of the coronary artery in rats. The most effective dose of 100.0 mg/kg, which is studying the connection was not different in effect from a drug comparison of inderal taken is th at a dose of 1.0 mg/kg
3.1.3. The effect of compound I on cardiohemodynamic intact rats and rats with acute myocardial ischemia.
The experiments were performed on the nonlinear rats male weighing 250-500 g, anesthetized with atenalol sodium (40 mg/kg intravenously). Experimental animals were placed on a controlled breath, opened the chest, pericardium and functionali the left ventricle at the apex of the heart. Intraventricular pressure and systemic arterial pressure in the carotid artery was detected by sensors Bentley. Using a differentiating device recorded the speed of contraction (dp/dt)maxand the rate of relaxation (dp/dt)minthe left ventricle of the heart. Heart rate was calculated by the R-R intervals-on the ECG, which was registered in the II standard lead. These indicators were installed in the intact rats and in animals with experimental myocardial infarction. Myocardial infarction caused by ligation of the left coronary artery at the level of its middle third.
At the first stage of the research studied the effect of compound I on cardiohemodynamic intact rats when administered intravenously in a dose of 5 mg/kg As can be seen from the data presented in table. 3, the connection I had caused increased contractility of the myocardium, which during the entire observation period was higher than in control. Analyzed Obedinenie increased and the level of mean arterial pressure (GARDEN), which exceeded the targets set in the control. Heart rate (HR) were not significantly changed.
In the setting of acute myocardial ischemia (table. 4) intravenous administration of compound I with positive effects on performance kardeogemodyinamiki. The cardioprotective effect of the substance was kept for 30 min from the beginning of the experiment. In the setting of acute myocardial ischemia introduction of compound I did not cause significant changes in heart rate.
3.1.4. The effect of compound I during acute myocardial ischemia in dogs.
Experiments put on mongrel dogs of both sexes weighing 14-18 kg Anesthetized with atenalol sodium (40 mg/kg intraperitoneally) dogs were intubated, transferred to a controlled breath using volumetric respirator “Vita”, layers opened the chest, removing the third and fourth rib on the left, the pericardium, the cut edges of which were attached to the edges of the wound. Under separated on a small segment of the artery of the first order from the system interventricular branch of the left coronary artery was summed up two ligatures. After injection of heparin (500 units/kg) 2-4 mm below the expected level of ligation of the coronary artery was injected into the vein plastic catheter, which was recorded by a ligature, summed atraumatic needle. Then made the selection venous blood and for determination of biochemical parameters (initial level). After ligation of the coronary artery was katatrophale distal her plot to determine the level of collateral coronary blood flow and retrograde pressure.
From the data presented in table. 5, it follows that in the control series of experiments within 60 min after occlusion of the coronary artery (CMOS) observed progressive negative shifts indicators kardeogemodyinamiki, poor blood supply to the ischemic myocardium, the formation of regional metabolic acidosis and increase the degree of kurtosis-lactate.
Intravenous administration of compound I in a dose of 100 mg/kg in 5 min after the EYE has increased the contractility of the heart muscle, the stabilization of the GARDEN, improving blood supply to the ischemic area of the myocardium. Comparison drug inderal intravenous dose of 1 mg/kg in 5 min after the EYE, also reduced the level of acidification of the blood, flowing from the zone of ischemia, and reduced the level of kurtosis-lactate. However, these positive biochemical changes in contrast to the effect of compound I was observed on the background of significant bradycardia, reduction of ischemic myocardium contractility, hypotension and deterioration of blood supply to the ischemic area of the myocardium.
3.2. Antiarrhythmic activity of the compounds I.
Experiments were performed on 56 Mature bisexual Wistar rats weighing 10-240 g, anesthetized vnutribruchinnah injection of sodium thiopental dose of 50 mg/kg
Compound I was administered intravenously, inkjet, simultaneously in doses of 5 and 20 mg/kg for 5 min prior to occlusion of a coronary artery. The Comparators lidocaine (2.5 and 5 mg/kg) and inderal (0.5 and 1 mg/kg) was administered intravenously immediately before the EYE.
The results of the study antiarrhythmic activity of compound I in a model of acute occlusive arrhythmias are presented in table. 6.
In the control series of experiment in all experimental animals through 249±33 seconds after the EYE arose polytopia ventricular premature beats and episodes of ventricular tachycardia, which duration was 60±17 sec. Injection of compound 1 at a dose of 5 mg/kg over 5 min to acute coronariography had no prophylactic antiarrhythmic action on this model. With increasing doses of compound I 20 mg/kg number of PVCs decreased (p<0.05), and duration of ventricular tachycardia was 7.3±3,6 sec (p<0,05). The positive effect of compound 1 at a dose of 20 mg/kg expressed and that under its influence the latent period occlusive arrhythmias increased to 382±25 sec vs. 249±33 seconds in the control series of experiments. It should be noted that ventricular fibrillation on the background of drug action did not arise in any experience.
Lidocaine statistically significantly reduced the l the incidence of ventricular tachycardia and shorten the duration of attacks to 7±0.3 sec (p< 0.05), whereas on other parameters of influence is not exerted. Antiarrhythmic activity of lidocaine at a dose of 5 mg/kg was higher than that of the compounds, however, he had a dampening effect on atrioventricular conduction. Inderal more than 5 times reduced the number of ventricular extrasystoles occurring within 10 min of coronarography, and shortened the duration of bouts of tachycardia to 18±12 sec vs 60± 17 sec in the control series of experiments, however, as well as lidocaine, inhibited the conductivity of the atrioventricular node.
Thus, in a model of acute occlusive arrhythmias in rats the compound I in a dose of 20 mg/kg has expressed prophylactic antiarrhythmic and protivopellargnoe action, not giving activity inderal and lidocaine. It is important to emphasize that, in contrast to the Comparators connection I never had a dampening effect on the function of the conductivity of the cardiac muscle.
3.3. Hypolipidemic activity of the compounds I.
The experiment was performed on outbred rats male weighing 220-250 g Hyperlipidemia induced daily by oral administration to animals oil suspension containing 10% cholesterol and 1% holeva acid, for 10 days; the volume of injected slurry was 1 ml/100 g body weight. Compound I was administered during the same period at a dose of 1 mg/kg Pronounced hipol epidemically activity was evaluated by the degree of inhibition induced hyperlipidemia, determining serum total cholesterol (LDL-General), cholesterol in the atherogenic lipoprotein fractions of lipoproteins of low and very low density (LDL-C) and (LDL-VLDL)cholesterol, high density lipoprotein (HDL-C) and triglycerides.
As can be seen from the results given in table. 7, the effect of atherogenic diet is accompanied by increased level of LDL-General at the expense of atherogenic VLDL fraction. Cholesterol accumulation is observed against the background of sustained hypertriglyceridemia.
With the introduction of compound I triglyceride levels decreased by 33%, the content of cholesterol in the antiatherogenic HDL fraction increased by 28%and the hypocholesterolemic effect was realized by reducing LDL-VLDL. These data indicate the severity regulation of lipid concentration activity of compound I, it should be noted important cardioprotective means the ability of a compound to increase the level of HDL, which provides the reverse transport of cholesterol.
Thus, the claimed connection γ-hydroxypropylamino-5-hydroxynicotinate has combined anti-ischemic, anti-arrhythmic and hypolipidemic properties. A significant advantage of the inventive compounds before β-adrenoblokatorami is its ability to reduce the level three is lazaridou in the blood, while used in therapy of coronary artery disease inderal contributes to the accumulation of triglycerides and reducing the concentration of HDL, thereby increasing the risk of coronary atherosclerosis.
When you save the spectrum and severity of cardioprotective action of compound I is significantly less toxic (LD50more than 5000 mg/kg) compared with inderal and has no cardiodepressive properties, which significantly expands the scope of possible application in medicine for the prevention and treatment of coronary heart disease.
The effect of compound I on the threshold of myocardial ischemia in awake rabbits.
|Medication||Dose. mg/kg||Total number of experiments||Effect||The lack of effect||The effect duration, min|
The effect of compound I on the size of the zone of necrosis after 4 hours after occlusion of the coronary artery in rats (M±m)
|The ischemic area (in % to the total mass of the myocardium)||The area of necrosis (% of total|
the mass of the myocardium)
|The area of necrosis (in % to the area of ischemia)|
|Note: * - differences from control significant at p<0,05.|
The effect of compound I in a dose of 5 mgkg on cardiohemodynamic intact rats in an open chest (in percentage to the initial value (M±m) (n=10)
|The time from the start of the experiment, min||Registered parameters|
|Note:#- differences from baseline level significant at p<0,05;|
* - difference from control significant at p<0,05.
The effect of compound I in a dose of 5 mg/kg cardiohemodynamic rats with acute myocardial ischemia (in percentage to the initial value (M±m) (n=10)
|Time after OKA, min||Registered parameters|
|Note:#- differences from baseline level significant at p<0,05;|
* - difference from control significant at p<0,05.
Antiarrhythmic activity of compound I in the early postocclusion arrhythmias in rats (M±m).
|Conditions of experience||Dose, mg/kg||Qty animals||Latent p is the period, sec||The duration of a VT, s||Qty GA|
|Note: RE - infection is ckova arrythmia;
< / br>VT - ventricular tachycardia;|
Fi - ventricular fibrillation;
* - difference from control significant at p<0,05;
andthe drug causes disturbances of atrioventricular conduction.
The effect of compound I on cholesterol and triglycerides in the blood serum of rats with experimental hyperlipidemia (M±m) (n=8).
|Conditions of experience||Dose, mg/kg/day||Cholesterol, mg/100 ml||Triglycerides, mg/100 ml|
|The control (intact animals)||-||77,9±5,5||42,1±2,6||17,7±1,6||18,1±2,3||90,5±11,4|
|Atherogenic diet||-||of 101.4±5,5* (P<0,02)||45,0±3,8||23,4±2,7||33,0± 3,2* (p<0,01)||165,0±16,0* (P<0,01)|
|Atherogenic diet +I||1,0||107,5±3,2||57,7±2,6** (P<0,02)||27,5±1,2||22,3±2,6** (P<0,05)||byr111.4±12,8** (P<0,05)|
|Note: * significance of differences with the data of the control group; < / br>**-significance of differences between data groups of animals with experimental hyperlipidemia.|
with anti-ischemic, anti-arrhythmic and hypolipidemic activity.
-OR SIG6N(R7)-, where R6- alkyl, R5choose from the group of alkyl, aryl, including heteroaryl, -COR7, -SO2R7and-COR10where R7Is H, alkyl or aryl, including heteroaryl, R2Is F, Cl, Br, J, alkyl, aryl, including heteroaryl, formyl, acyl, C(O)NR7R10or C(O)or SIG7, m = 0, 1, or 2, R3selected from the group comprising R7OR7N(R7)(R10) and CH(R7)C(O)R8, R8is R7OR7and NR7R10, R9is hydrogen, alkyl, aryl, including heteroaryl, -C(O)R10, -SO2R10, -C(S)OTHER10, -C(NH)NH(R10), -C(O)OTHER10, R10- H, alkyl, or aryl, including heteroaryl, and in each case, it is not necessarily different from R7X represents an ion halogen provided that 1) when two alkyl groups are the same carbon or nitrogen, they are not necessarily linked together with the formation of a cyclic structure, and (2) nitrogen heteroaryl ring R1
< / BR>where AG represents a radical selected from formulas (a) and (b) below:
< / BR>R1represents a halogen atom, -CH3CH2OR SIG7, -OR SIG7, СОR8, R2and R3taken together form a 5 - or 6-membered ring, R4and R5represent H, a halogen atom, a C1-C10-alkyl, R7represents H, R8represents H orX represents the radical-Y-C-, r' and r" is H, C1-C10alkyl, phenyl, Y represents S(O)nor SE, n = 0, 1, or 2, and salts of compounds of formula (I)
FIELD: medicine, cardiology.
SUBSTANCE: traditional therapy of myocardial infarction should be supplemented with granocyte introduced either subcutaneously or intravenously at the dosage of 0.48 mln IU/kg body weight daily for 5 d.
EFFECT: higher efficiency of therapy.
FIELD: medicine, cardiology.
SUBSTANCE: patient with stenocardia should be introduced with efficient quantity of omapathrylate or its pharmaceutically acceptable salt either separately or in combination with another pharmaceutically active agent. Another pharmaceutically active substance could be represented by organic nitrate, beta-adrenergistic blocking agent, blocking agent of calcium supply or antithrombocytic preparation. It is suggested to apply omapathrylate or its pharmaceutically acceptable salt to prepare medicinal preparations for treating and/or decreasing stenocardial symptoms.
EFFECT: higher efficiency.
16 cl, 2 dwg, 2 ex, 8 tbl
FIELD: medicine, ophthalmology.
SUBSTANCE: one should introduce 1.0% serotonin adipinate solution intravenously due to infusion once daily for 10-12 d. The method enables to increase visual functions due to decreased tissue hypoxia and normalization of retinal microcirculation, resorption of hemorrhages, reverse development of retinal edema, normalization of functional thrombocytic activity and hemostatic values.
EFFECT: higher efficiency for therapy.
FIELD: medicine, cardiology.
SUBSTANCE: the suggested method should be performed at the background of medicinal therapy with preparations out of statins group, tevetene, polyoxidonium and conducting seances of plasmapheresis by removing 800 ml plasma twice weekly with N 5 due to additional intramuscular injection of immunophan 0.005%-1.0 with N 10 and fluimucyl 300 mg intravenously daily with N 5-10, total course of therapy lasts for 2 mo. The method provides modulation of leukocytic functional activity, moreover, due to altered cytokine profile and, thus, through disintegration of protein-lipid complexes participating in the development of atherosclerotic platelets.
EFFECT: higher efficiency of therapy.
FIELD: organic chemistry, medicine, chemical-pharmaceutical industry, pharmacology, pharmacy.
SUBSTANCE: invention relates to a medicinal agent used for prophylaxis and treatment of diseases and disorders associated with dysfunction of benzodiazepine receptors. This medicinal agent comprises compound of the formula (I)
. Compound of the formula (I) elicits high cardioprotective, neurotrophic, renoprotective activity and enhanced bioavailability.
EFFECT: valuable medicinal properties of compounds.
5 cl, 1 tbl, 1 ex
R1means alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms; CandH2A-phenyl, where a = 0, which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, Br, J, CF3, metoxygroup; CdH2d(C3-7-cycloalkyl, where d = 0; R2and R3independently from each other denote hydrogen, F, Cl, J, C=N; COR6where R6denotes hydrogen, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms, OR30where R30- alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms; OR7where R7denotes hydrogen, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms; phenyl; or R2and R3, independently of one another, denote CqH2q-phenyl, where q=0; or R2and R3independently from each other mean-SOnR22where n stands for zero, R22- alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms; R4and R5independently of one another denote hydrogen, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms, F, Cl, Br, J, CF3and their physiologically acceptable salts; and to medicines, inhibiting Na+dependent Cl-/HCO-3- exchange rate is
where R and R1have the meanings indicated in the claims