A means with antiischemic, hypotensive, antiarrhythmic and nootropic activity

 

The product contains 3-phenyl-4-aminobutyric acid and glutamic or nicotinic acid. The molar ratio of 3-phenyl-4-aminobutyric acid and the carboxylic acid is (1-3):1. The tool is low-toxic, has expressed antianginal and antiarrhythmic action, lowers blood pressure, has a neuroprotective effect, in particular improves the formation and reproduction memorable track in normal conditions and in conditions poststorage amnesia, has antiamnesic action. 8 table.

The invention relates to pharmaceutical industry and medicine and relates to products containing derivatives of gamma-aminobutyric acid and affect the cardiovascular system.

There are many different medicines, which have anti-ischemic, hypotensive and antiarrhythmic activity. However, the wide distribution and variety of cardiovascular diseases makes the search for new funds actual problem.

The important role of gamma-aminobutyric acid (GABA) in the regulation of the circulatory system, including coronary and cerebral, attracts researchers to search for new tools to ensure the ISU is funaho steps.

Currently in practical medicine is widely used by a number of GABA derivatives: acid, baclofen, pikamilon, piracetam, phenibut. Drugs improve cerebral and coronary circulation, have antianginal, antiarrhythmic and protivoparazitarnymi properties. However, for the treatment of hypertension not recommended.

Known hypotensive (and.with. The USSR 797219), antihypoxic activity (Y. G. Bobkov and other Pharmacological characterization of a new phenyl analogue of piracetam - 4-phenylpiracetam //bul. The experts. Biology and medicine. 1983. The HSU. S. 50-53) and anti-ischemic effect of N-carbarnoyl-4-phenyl-2-pyrrolidone (Evraz. application 199900878/26. Bull. 1, 2001). Antiarrhythmic action of this compound is not described.

It is known that succinic acid and its salts possess adaptogenic ability and have antihypoxic, anti-stress and neurotropic activity, normalize energy metabolism. It is also known cardioprotective and anti-ischemic action of succinic acid (Succinic acid in medicine, food industry, agriculture. Collection of scientific articles. Pushchino. 1997). Described (patent RF 2108095, a 61 K 31/19, published. 1998.04.10) drug for the treatment of brain ischemia, with whom icii, contains succinic acid and other active ingredients. For example, described antihypoxic agent containing as an active substance 3,5-diamino-1,2,3-thiadiazole and succinic acid (RF patent 2096043, published. 1997.11.20 And 61 To 47/03), its anti-ischemic and anti-hypertensive action is not known. It is known tool that has anti-ischemic, anti-hypertensive and antihypoxic activity (application 199900877. Bull. The Eurasian patent office 1-2001, publ. 26.02.01), including N-carbarnoyl-4-phenyl-2-pyrrolidone (CFP) and two - or trehosnovnoy carboxylic acid. As a dibasic acid is used or oxalic acid, or malic or succinic acid, as trehosnovnoy lemon. The proposed drug exceeds the efficiency of N-carbarnoyl-4-phenyl-2-pyrrolidone and a number of well-known drugs used as reference Comparators. Antiarrhythmic action of these means are not described.

Closest to the proposed drug PHENIBUT (encyclopedia of drugs. 2000 S. 963), representing hydrochloride beta-phenyl-gamma-aminobutyric acid. Compared with other derivatives of GABA he has a superior ability to penetrate the BBB and recommended to inogo pressure (BP) in the range of doses above 30 mg/kg and can be recommended as antihypertensive drugs for the treatment of hypertension with vascular dystonia in children and adolescents, persons suffering from the initial stages of hypertensive disease (E. I. Volchansk. //All-Union Symposium Phenibut and substituted GABA. The abstracts. Cheboksary. 1981 S. 107-112). Affects the performance of cardiac activity and blood circulation (S. A. Nikitin, etc. ibid, p. 104-107.), it has high anti-stress and antioxidant activity (R. U. Ostrovskaya, etc. //Mechanism of action and clinic derivative of gamma-aminobutyric acid. Scientific notes of the University of Tartu. Tartu. 1984. C. 46-59). Antiischemic and antiarrhythmic activity not described.

The objective of the invention is to obtain an effective low-toxicity drug on the basis of 4-amino-3-phenylbutanoate acid having a high anti-ischemic, hypotensive, antiarrhythmic and nootropic activity, improved ability to penetrate into the brain, to expand the range of such tools.

The task is implemented by the proposed remedy, including 4-amino-3-phenylbutanoate acid (FBA) and carboxylic acid. As carboxylic use of glutamic or nicotinic acid. Moreover, the ratio of 4-amino-3-phenylbutanoate acid (FBA):carboxylic acid as (1-3):1.

It means, onania.

The invention is illustrated by the following example.

Example.

Ball mill load the appropriate quantity of 4-amino-3-phenylbutanoate acid (FBA) and carboxylic acid. The mixture was thoroughly stirred for 0.5 to 1 hour, and then upload the resulting product.

The number of components is given in table. And at the end of the description.

The quantitative output thus Obtained funds were studied in experiments on animals.

Acute toxicity was determined on white mice with intraperitoneal injection. Survival of animals was assessed after 24 hours. Received the following LD50 values: Index composition 51 - 1614,73 (1516,80-1718,92) mg/kg, the Index composition 52 - 2010,48 (1851,13-2183,54) mg/kg, Phenibut - 1324,59 (1184,12-1481,73) mg/kg Study of the antihypertensive effect study of the antihypertensive activity conducted experiments on shot (eleminal-sodium 40 mg/kg/br) cats with intravenous researched substances in doses of 25 and 50 mg/kg Systemic blood pressure (SBP) was recorded in the carotid artery, and heart rate (HR) - cardiogram in the second standard lead. Change the main hemodynamic parameters were recorded by the method of integral rheography of the body (I. I. Tishchenko in mo the arterial pressure. Drums (CRM) and minute amounts of blood (IOC) was decreased to 60 minute observations at the 10%, total peripheral resistance vessels (SVR) increased by 8.4%, the heart rate remained practically unchanged. At a dose of 50 mg/kg tool - 151 caused prolonged (>3 hours) reduction in blood pressure (14.5 to 18.5%), reaching maximum values at 60 minutes. There was an increase of WALK (21-24,4%) in severe bradycardia (24-25,2%). IOC in this regard was reduced by 11.5%. There were minor peripheral vasodilatation (10,7% relative to the background value).

Tool - 52 (SFP+glutamic acid) at a dose of 25 mg/kg did not significantly affect hemodynamic parameters. HELL slightly (11.6%) was increased due to the constriction of peripheral vessels (by 23.7% compared with the background). The WALK was decreased by 10.4% at constant heart rate, resulting in the IOC also fell (by 13.5%). At a dose of 50 mg/kg were recorded distinct hypotensive effect (22,9%) caused a significant decrease in SVR (31.1%), while increasing shock and minute amounts of blood (32 and 18.8%, respectively). However, shifts wore a phase nature and on the 45th minute was observed depression of these indicators. From this moment until the end of the study is to achieve IOC (23.3%) against the background of recovery values and outlines actions to the initial level.

Thus, the result issledovaniya offer funds found that they exhibit hypotensive activity, while the tool - 52 51 more.

The study of anti-ischemic actions the impact of the new salts on the functional state of the hearth myocardial ischemia was investigated in experiments on anesthetized (eleminal-sodium 40 mg/kg/br) cats. When ischemia was simulated occlusion (5 and 30 minutes) of the descending branch of the left coronary artery in the middle third (G Agricultural Goldstein, 1984). Antianginal activity was assessed by the depression of the total value of ST-segment epicardial electrogram registered with 3 points of the surface of the heart. Comparators were obzidan (0.25 mg/kg) and verapamil (0.25 mg/kg). Summarized data on the impact of new analogues of phenibut on the functional state of the hearth myocardial ischemia are presented in table. 1 and 2.

Preventive introducing the compound 51 (50 mg/kg) was limitirovala increase the total value of the ST segment, and the maximum value (42.9% relative to control values) were recorded for 5 min (at 5-minute ligation of the coronary artery) and 30 minute (63.8%) at 30-minute ligation (PL. 1, 2).

In conditions of acute isegonda ST epicardial electrogram maximum of 35.9% for 1 minute occlusion in the 5-minute ligation. Return indicators to background values were observed at 3 minutes of re-oxygenation. In terms of the 30-minute occlusion for 30 minutes the magnitude of the ST segment was lower than in animals of the control group 56.9%, after removal of the occlusion of the coronary artery recovery of ST segment to baseline was observed only at the 30th minute (PL. 1, 2).

The Comparators verapamil and obzidan in the 5-minute occlusion reduces the magnitude of the ST segment, respectively, by 45.6% and 37.1%, recovery of ST segment to baseline occurs 5 minutes after the re-oxygenation. In terms of the 30-minute occlusion after pretreatment with verapamil and obsidan the ST segment decreased by 67.2% and 53.5%. The restoration of the ST segment in the conditions of reperfusion occurs 5 minute (verapamil) and 30 minute (obzidan) (table. 3, 6).

Phenibut dose of 36.4 mg/kg in the 5-minute occlusion prevents the growth of the total value of ST segment maximum of 26% compared with the control group. When the 30-minute occlusion of a coronary artery, the magnitude of ST segment decreased by 39.6% (table. 3, 6).

Thus, the proposed tools in varying degrees, increase the tolerance of the myocardium to ischemia. Moreover, the means 51 for antiischemic reperfusion ventricular cardiac rhythm was studied in experiments on anesthetized (eleminal-sodium 40 mg/kg/br.) cats in conditions of controlled breathing. After thoracotomy was performed occlusion on the border of upper and middle third of the descending branch of the left coronary artery. After 30 minutes of occlusion shot that induced in animals reperfusion ventricular arrhythmias (I. E. Herzenstein et al., 1990, Parrat, Cocer, 1984). The study drugs were injected in/in slowly for 10 min prior to occlusion. Ventricular fibrillation was assessed by electrocardiogram.

Continuou model of cardiac arrhythmias or atrial-ventricular shape arrhythmia reproduced according to the method described by N. In.Kaverina and H. P. Sinoway (1981). Aconitin was administered at a dose of 40 mcg/kg analyte was injected 10 min before the injection of aconitine. Antiarrhythmic effect was assessed by the number fibrillyatsy and death.

Chloralkali model arrhythmia caused intravenous 10% solution of calcium chloride (300 mg/kg) according to the method of M. Malinow et al. (1953). The experiments were performed on anesthetized rats. The substance was administered at a dose of 50 mg/kg for 10 min prior to the introduction of aritmogeni.

Comparators in this series of studies were obzidan and verapamil (0.25 mg/kg).

In the control series of experiments after reperfusion in 100% of cases were recorded various arrhythmias, passing in 87.5% of cases in F. the definition of verapamil and obsidan in doses of 0.25 mg/kg/warned appearance fibrillyatsy ventricles by 54.2% and was significantly reduced mortality, accordingly, by 54.2 and 70.8% (table. 3).

Tool - 51 at a dose of 50 mg/kg in significantly compared to the control reduced the total number of arrhythmias, their severity, and increased the survival rate of experimental animals with acute coronariography and reperfusion (table. 3).

The tool 52 in a dose of 50 mg/kg/practically never warned of cardiac arrhythmias caused by reoxygenating attack. So in 66.7% of cases there were life-threatening arrhythmia, which, along with tachycardia, ventricular extrasystoles, and paroxysmal ventricular tachysystole developed bouts of atrial fibrillation, and in 50% of sudden death from ventricular fibrillation of the heart (table. 3).

Thus, the study of antiarrhythmic and protivopellargnoe activity new funds for reperfusion model arrhythmias showed that the tool - 51 effectively prevents the development of gross arrhythmias, including ventricular fibrillation and increases survival of animals during reperfusion.

On aconitine model of cardiac arrhythmias (LDCs) in the control series of experiments in animals in 100% of cases there was the death of animals, while severe forms of LDCs, such as ventricular taxicard the numerical ventricular premature beats on the background of bradycardia and cardiac arrest (table. 4).

In the group of animals treated for 15 min prior to the introduction of aconitine verapamil and obzidan in doses of 0.25 mg/kg/arrhythmias developed in 100%, including 40% of cases of ventricular tachysystole and fibrillation. However, mortality was recorded only 20%, which was significantly lower than in the control group (table. 4).

The studied preparations in doses of 50 mg/kg/turned out to be almost ineffective in this model, arrhythmias (table. 4).

In the control series of experiments, the introduction of 200 mg/kg/CaCl2caused various arrhythmias, including frequent ventricular extrasystoles, paroxysmal tachysystole and fibrillation of the heart, respectively, 30 and 80%. In General, rough rhythm disturbances, which led to the deaths of animals, developed in 90% of cases (table. 5).

On chloralkali model LDCs verapamil and obzidan in doses of 0.25 mg/kg/caused pronounced antiarrhythmic and protivopellargnoe action. So, ventricular fibrillation and mortality were observed, respectively, 40 and 20%, which was significantly lower than in control. 20 and 80% of cases of arrhythmia was absent (PL. 5).

The studied preparations in doses of 50 mg/kg/also prevented development of arrhythmias caused by the introduction l2, one of the calcium model arrhythmias proposed funds showed a pronounced antiarrhythmic effect, however, a few inferior in efficiency to the Comparators.

The influence of basic hemodynamics in acute myocardial ischemia Experiments were performed on anesthetized (eleminal-sodium 40 mg/kg/br) cats. Ischemia was simulated occlusion (5 and 30 minutes) of the descending branch of the left coronary artery (ANULKA) in the middle third. Systemic arterial pressure was recorded in the usual way in the carotid artery, the heart rate by electrocardiogram (ECG) in the second standard lead. Impact on key indicators of kardeogemodyinamiki investigated by the method of tetrapolar rheography of the body (I. I. Tishchenko modification S. A. Nikitin and I. A. Orbinski) and by the method of electromagnetic flametree (C. C. Zaretsky et al., 1974). On the basis of the analysis phase curve of the blood flow in the ascending part of the aortic arch (Spencer, Greiss, 1962) has identified the following indicators or indices of hemodynamics and heart: HELL; HR; WALK IOC; the CSO and intraventricular pressure (VID).

In the control series of experiments on the 30th minute of coronarography there was a significant decrease in the level of the GARDEN (21%) due to significant reduction of shock and minute amounts of blood, power, left the resistance (31%). Such shifts cardio - and hemodynamics, likely due to the decrease in the pumping function of the heart and compensatory contraction of the peripheral vessels, which can lead to the violation of the collateral circulation and the sharp deterioration of blood supply subendocardialnah layers of the heart muscle.

Hemodynamics of animals treated before ligation of the coronary artery verapamil and obzidan in doses of 0.25 mg/kg/in, changed significantly less than in control. So, level GARDEN, drums and minute volume of blood circulation, indicators Mlj 30 minute acute myocardial ischemia decreased, respectively, 17% and 15%, 18 and 22%, 25% and 39%, 16% and 35%, and SVR was increased by 8% and 24%, which was significantly lower than in control experiments.

The introduction of means - 51 at a dose of 50 mg/kg resulted in a pronounced reduction of violations by systemic hemodynamics in terms of coronarography. So, percussion and minute amounts of blood flow decreased, respectively, 16% and 27%, the capacity of the left ventricle decreased by 18%, virtually unchanged SVR.

The tool 52 is slightly warned of the negative changes in the system cardio hemodynamics caused ANULKA).

Thus, the proposed tools in doses of 50 mg/kg in the call report is on invertirovannoi heart and restriction zone of necrotic damage.

The study of the neuroprotective activity
Evaluation of the neuroprotective activity of the investigated tools was conducted on the following models:
- conditional reaction passive avoidance (passive avoidance reaction) to assess the impact on learning and fixation memorial trail;
- amnesia passive avoidance reaction caused by electroshock (ACS) to estimate antiamnesic activity of substances.

Methods in accordance with which conducted the experiments described in the section "guidelines for the study of the neuroprotective activity of pharmacological substances" (editors: D. M. N., Professor T. A. Voronina, D. M. N.; Professor R. U. Ostrovskaya) in the book Manual on experimental (preclinical) study of new pharmacological substances. M., 2000. - S. 153-158.

The setup for the experiment passive avoidance reaction consists of two adjacent compartments, one of which is large (HH cm), open at the top and illuminated (90 Lux), the other is smaller (HH cm), is dark, closed on all sides with the rectangular hole (8x8 cm) for a message with a large compartment and electrified floor. The method consisted of two stages: training the skill and play it safe. 30 minutes before training the animals of the experimental groups were injected analyte. In lying to the compartment. Then recorded the latent period of the first entry into the dark compartment (the time from placing the animal in the middle of the court before the first entry into the dark compartment), the total observation time of 3 minutes (the animals, not calling in a dark chamber during this time, from experience excluded). After each time in the dark compartment, the animal was put electrobalance irritation (40, 3 pulses for 1 s, with an interval of 0.5 sec). Produced registration number of entries into the dark compartment. Play skill passive avoidance reaction was performed on the following day (24 hours) after training (the second day of the experiment). Playback procedure and the recorded parameters corresponded to those in training, with the only difference that was not made electrovalve stimulation of the animal and recorded the total time spent by the animal in a dark compartment. On the first day of the experiment it was noted the following indicators: the number of entries into the dark compartment, the indicator reflecting the learning abilities of animals (less turns, the faster the learning process) and the latent period of the first entry for comparison with the same period after training. On the second day of the experiment recorded the latent period of the first entry, in which the degree of preservation of traces in the memory, the number of entries into the dark compartment for comparison with the same period the first day of the experiment, as well as the total time spent in the dark compartment (less than a specified time, the more secure is a memorable track). The reduction in the number of visits in a dark compartment in animals treated with the substance under study, compared to control was seen as a positive effect on the speed of learning processes (the first day of the experiment). The increase in the latent period of the first entry of the animal into the dark compartment during playback compared to the latent period of the first entry to training, as well as reducing the number of entries into the dark compartment and the total time spent in it animals of the experimental group compared with control was regarded as a positive effect of the substance on the fixation and strength save traces in the memory.

The effect of the studied compounds on the processes of memory and learning after the amnestic effects were studied in the test "amnesia passive avoidance reaction caused by electroshock". Amnesia was called (on the second day of the experiment) maximum electroshock conducted transcorneal immediately (within 30 minutes) after production of passive avoidance reaction (110 V, 50 Hz, 20 mA, 0.5 s). Play p is to reduce the latency time of entry into the dark compartment and increase the time spent in the dark compartment. On the first day of the experiment was of interest, the following indicators: the number of entries into the dark compartment and the latent period of the first entry for comparison with similar performance after training. On the second day of the experiment recorded the latent period of the first entry, which in comparison with the similar indicator of the first day of the experiment indicates the degree of preservation of traces in the memory, the number of entries into the dark compartment for comparison with the same period the first day of the experiment, as well as the total time spent in the dark compartment. Antiamnesic effect in all cases is expressed in removing amazonvideo actions ECS, which is characterized by an increase in the latent period of time in a dark chamber, a decrease in the number of visits in a dark compartment and decrease the time spent in the dark chamber when playing a reflex.

The experiments were carried out on outbred rats females six months of age, weighing 180-200 g (5 experimental groups of 10 animals in each group). The experimental group received the phenibut and 2 new tools, the preparation of the positive control piracetam (20% aq for injection), the results were compared with the control group.

Substance waybut dose of 36.4 mg/kg and saline solution (control group) was administered 30 minutes prior to training intraperitoneally in equal volumes. The results of the experiments were processed by methods of basic statistical analysis STATISTICA software/w5.0 company StatSoft, Inc., (USA) for Windows. Summarized data are presented in tables 6, 7.

Means, including FBA and nicotinic acid - 51, practically did not affect the counts of animals in a dark chamber on the first day (training day) in the test passive avoidance reaction. On the second day of the experiment (day playing skill passive avoidance reaction) test substance significantly (p<0,05) increased the latent period of time in a dark cell, 3.6 times reduced the number of calls of animals in a dark chamber in comparison with the first day of the experiment (p<0.01), and 1.7 times reduced the time spent by animals in the dark chamber (PL. 6). Through the study of its antiamnesic activity in the test "amnesia passive avoidance reaction caused by electric current" revealed an increase (compared with control) latent period of entry of animals into the dark compartment and a significant decrease in the number of calls of animals in the dark compartment after modeling amnesia (p<0,05), but the time spent by animals in the dark camera (compared to control) was almost unchanged (table. 6). The data obtained indicate that the tool - 51 clearly had no effect on the speed of learning, but improved fix the STV approach animals in a dark chamber in the test passive avoidance reaction in the first day (training day), but significantly (p<0,01) increased the latent period of the entries in a dark chamber on the second day (day playing skill passive avoidance reaction); reduced the number of calls of animals in a dark chamber in comparison with the first day of the experiment (2-fold, p<0.05), reduced the time spent by animals in the dark camera (1.6-fold, p<0,05) (table. 6). Through the study of its antiamnesic activity revealed a significant (p<0.05) increase in the latent period of the entry of animals into the dark compartment and reducing the number of calls of animals in the dark compartment after modeling amnesia (p<0,01). The time spent by animals in the dark chamber was decreased by 1.3 times compared to the control, but this figure has not changed significantly (table. 7). Thus, the tool 52 has a positive effect on memory (in particular, on the processes of fixation memorable track) and has antiamnesic effect.

We investigated the funds identified neuroprotective action, but after the power of expression of neuroprotective action of these compounds do not differ from phenibut and pyracetam.

Thus, the proposed tools are less toxic than the original substances have a more pronounced antianginal and antiarrhythmic action, reduce blood pressure, and have the s poststorage amnesia, have antiamnesic action.


Claims

A means with antiischemic, hypotensive, antiarrhythmic and nootropic activity, characterized in that it includes 3-phenyl-4-aminobutyric acid and glutamic or nicotinic acid, with the molar ratio of 3-phenyl-4-aminobutyric acid and the carboxylic acid is (1-3): 1.

 

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