Dicyclohexylamine n-substituted-aminocarbonyl acids possessing antiarrhythmic and antifibrillatory 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 biological compounds, namely dicyclohexylamine N-substituted-aminocarbonyl acids of the General formula given in the description. The claimed compounds have a pronounced antiarrhythmic and antifibrillatory activity and differ from the known antiarrhythmic drugs that combine the properties of antiaritmikov class I and class III. 3 tab., 2 Il. The invention relates to a new group of biologically active chemical compounds, namely dicyclohexylamine N-substituted-aminocarbonyl acids of General formula I
< / BR>where R1hydrogen or lower alkyl, R2and R3- same or different, hydrogen, lower alkyl, oxyalkyl, aminoethyl, cyclohexyl, or R2and R3along with carrying their nitrogen atom are rich heterocycle having one or two heteroatoms and their pharmaceutically acceptable acid salt of accession, as well as Quaternary salts.A known number of Lekarstvo is give N-substituted-aminocarbonyl acids, for example, lidocaine, procainamide, piromekain etc. These drugs, belonging to the modern classification of drugs for the treatment of cardiac arrhythmias , belong to the first class. Drugs of this class have a small therapeutic latitude due to the relatively high toxicity, explain the main mechanism of action of these drugs block sodium channels.Of greatest interest to clinicians currently represent a drugs class III antiarrhythmic actions.These drugs prolong the action potential of myocardial cells, the basis of their effect is the effect on potassium channels. To date, there are enough good antiaritmikov this class. The most famous representatives of the class III amiodarone  and sotalol  have numerous side effects that preclude their long-term use . The newly established drug sematilide (N-(2-diethylaminoethyl)-4-(methylsulfonylamino)benzamide HCl  the closest to the claimed substances antiarrhythmic action. However, he does not have enough high efficiency and therapeutic latitude. Due to the fact that drugs class III may have wide application in therapik in our country, and in several foreign countries.Thus, despite the abundance of antiarrhythmic drugs the clinic still needs new, more efficient and generic drugs, which with good pharmacokinetic properties would not cause negative side effects.The aim of the present invention to provide a new series of substances with the highest antiarrhythmic and antifibrillatory activity with great therapeutic breadth and combining properties of antiaritmikov class I to class III.In accordance with the invention of a new chemical group of substances - dicyclohexylamine N-substituted--aminocarbonyl acids of General formula I, where R1to R3have the previously mentioned meanings, and their physiologically acceptable acid salt of accession and their Quaternary salts having the properties of antiaritmikov class I and class III.Compounds of General formula I in special and patent literature to date has not been described.As examples for compounds of formula I of the present invention should be called:
1 - dicyclohexylamine Diethylaminoethanol acid hydrochloride;
the th acid bromo-propene-2-ilat;
4 - dicyclohexylamine(diethylamino) propionic acid hydrochloride;
5 - dicyclohexylamine bis-(2-hydroxyethyl) aminouksusnoy acid;
6 - dicyclohexylamine bis-(2-hydroxyethyl) aminouksusnoy acid hydrochloride;
7 - dicyclohexylamine bis-(2-hydroxyethyl)--aminopropionic acid hydrochloride;
8 - dicyclohexylamine morpholinoethoxy acid;
9 - dicyclohexylamine morpholinoethoxy acid hydrochloride;
10 - dicyclohexylamine hexamethyldisiloxane acid hydrochloride;
11 - dicyclohexylamine octahedral(1,2-a)- pyrazinone acid dihydrochloride;
12 - dicyclohexylamine butylaminoethyl acid hydrochloride;
13 - dicyclohexylamine ISO-butylaminoethyl acid hydrochloride;
14 - dicyclohexylamine -(N-butylamino) propionic acid hydrochloride;
15 - dicyclohexylamine cyclohexasiloxane acid hydrochloride;
16 - dicyclohexylamine aminouksusnoy acid hydrochloride hydrate;
17 - dicyclohexylamine (2-amino-ethyl) aminouksusnoy acid dihydrochloride.Thus, the claimed group of substances of General formula I prototype on chemical structure is not described.As preparations the sa and the drug sematilide, which refers to antiaritmikam class III. The choice of these drugs is associated with the fact that the compounds of the claimed group combines the properties of antiaritmikov class I and III.The synthesis of the inventive compounds I and IV is carried out by the interaction of dicyclohexylamine-halogencarbonic acid II with primary, secondary, heterocyclic amines III and subsequent conversion of the obtained bases I into the corresponding acid salt of joining or Quaternary salt (IV) according to the following scheme:
< / BR>where
Hal = Cl or Br
IV.1 R1=H, R2=R3=C2H5, R4=H, x = Cl
IV.2 R1=H, R2=R3=C2H5, R4=CH3x = J
IV.3 R1=H, R2=R3=C2H5, R4=CH2CH=CH2x = Br
IV.4 R1=CH3, R2=R3=C2H5, R4=H, x = Cl
IV.5 R1=H, R2=R3=CH2CH2OH, R4=H, x = Cl
IV.6 R1=CH3, R2=R3=CH2CH2OH, R4=H, x = Cl
IV.7 R1=H , R4=H, x = Cl
IV.8 R1=H , R4=H, x = Cl
IV.9 R1=H , R4=H, x = Cl
IV.10 R1=R2=H, R3=H-C4H9, R4=H, x = Cl
IV.11 R1=R2=H, R3=CH2IV.13 R1=R2=H, R3=C6H11, R4=H, x = Cl
IV.14 R1=R2=H, R3=CH2CH2NH2, R4=H, x = Cl
IV.15 R1=R2=R3=R4=H, x = Cl
Dicyclohexylamine N-substituted - aminocarbonyl acids I received boiling amides I with an excess of the appropriate amine III without solvent or in a medium of an organic solvent with a yield of 50-60% of theory. As solvents can be used alcohol, benzene, toluene, and other Conditions of the reactions depend on the structure of the original amine and the boiling temperature of the solvent. The amide I are crystalline or oily substances the main character. Purity was monitored by thin layer chromatography on DC Alufolien Kieselgel 60 F 254 in the system benzene: ethanol: aqueous ammonia (8:2:0,1). The Rf Value Of 0.24-0,58.Under the action of inorganic acids, for example hydrochloric acid, amides I give acid salt accession (IV.1, IV.4-IV.15), when the action iodotope bromide or allyl bromide to give the Quaternary salt (IV.2, IV.3). The structure of the salts IV proved by data of elemental analysis and spectral data. In the IR spectra taken in KBr plates, there are intensive strips buddy absorption is cm-1; characteristic of the hydroxy-group (IV.5, IV.6), and the absorption band 3496 cm-1characteristic amino group of the primary amine (IV.10).Salt IV are white crystalline substances sparingly soluble in water, soluble in alcohol, insoluble in ether, benzene.Below are examples of obtaining illustrating the claimed group of compounds. Example 1. Hydrochloride dicyclohexylamine Diethylaminoethanol acid (IV.1).The mixture 10,32 g (0.04 mol) of dicyclohexylamine Chloroacetic acid and 29,24 g (0.4 mol) of diethylamine boiled for 6 hours Excess diethylamine distilled off, the residue is washed with water and extracted with benzene. The benzene solution is washed twice with water and evaporated to dryness. The residue (oil) was dissolved in 70 ml of acetone, add concentrated hydrochloric acid to pH 1-2 and leave to stand overnight. The precipitate is filtered off, washed with acetone. Yield 6.6 g (50%). So pl. 221-222oC (decomp.) (from a mixture of absolute alcohol and acetone).Found,%: C 65,32; H 10,66, N 8,49; Cl Of 10.72. C18H35ClN2O.Calculated,%: C 65,33, H 10,66, N 8,46; Cl 10,71.Example 2. Yodmetilat of dicyclohexylamine Diethylaminoethanol acid, (IV.2).To a solution of 2 g of di is iodotope bromide in ether. Leave to stand overnight. The precipitate is filtered off. Yield 3.1 g (90%). So pl. 195-196oC (from acetone).Found,%: I 29,09, C19H37IN2O.Calculated,%: I 29,08.Example 3. Bromopropane-2-ilat of dicyclohexylamine Diethylaminoethanol acid (IV.3).To a solution 2,94 g (0.01 mol) of dicyclohexylamine Diethylaminoethanol acid (receipt, see example 1) in 25 ml of benzene was added 9 ml of allyl bromide and the reaction mixture is boiled for 5 hours the Precipitate is filtered off. The output of 2.1 (50,6%). So pl. 162-163oC (from a mixture of alcohol and ether).Found,%: C 60,46; H 9,43; N 6,48; Br 19,13. C21H39BrN2O.Calculated,%; C 60,71; H 9,46; N 6,74; Br 19,24.Example 4. Hydrochloride dicyclohexylamine diethylaminopropylamine acid (IV.4).3.2 g (0.01 mol) of dicyclohexylamine-bromopropionic acid is boiled in 10 ml of diethylamine 7 hours the Reaction mass is then cooled, poured into 100 ml of water. The aqueous solution is extracted with benzene, the benzene solution is evaporated to dryness. Oil (2.4 g) is dissolved in 25 ml of acetone, add ether saturated with hydrogen chloride to pH 1, leave to stand overnight. The precipitate is filtered off. Yield 1.92 g (51,31%). So pl. 222-223oC (decomp.) (from isopropyl alcohol).Neiderhiser 5. Hydrochloride dicyclohexylamine bis(2-hydroxyethyl) aminouksusnoy acid (IV.5).A mixture of 10.3 g (0.04 mol) of dicyclohexylamine Chloroacetic acid and 10.5 g (0.1 mol) of diethanolamine in 30 ml of absolute ethanol is boiled for 8 hours the Reaction mass is then cooled, poured into 350 ml of ice water and leave to stand overnight. The precipitate is filtered off, washed with water and dried. The yield of 13.7 g (94,5%), pl. 101-102oC.Found,%: C 66,34; H 10,52; N 8,65. C18H34N2O3< / BR>Calculated, %: C 66,22; H 10,5; N 8,58. 3 g of the base are dissolved in 30 ml of acetone, add concentrated hydrochloric acid to pH 1, leave to stand overnight. The precipitate is filtered off, washed with acetone, air-dried. Output hydrochloride IV.5 2.6 g (77,8%). So pl. 219-220oC (decomp.) (from isopropyl alcohol).Found,%: C 59,46; H 9,68; N 7,74; Cl 9,86. C18H35ClN2O3.Calculated,%: C 59,57; H 9,72, N 7,72; Cl 9,77.Example 6. Hydrochloride dicyclohexylamine bis-(2-hydroxyethyl) - aminopropionic acid (IV.6).The mixture between 6.08 g (0.02 mol) of dicyclohexylamine-bromopropionic acid and 5.25 g (0.05 mol) of diethanolamine in 30 ml of absolute ethanol is boiled for 8 hours After cooling the reaction was poured into water, extracted with benzene. Benzene is a second acid to pH 1-2 and leave to stand overnight. The precipitate is filtered off. Yield 5 g (66.3 per cent). So pl. 168-169oC (from a mixture of absolute alcohol and ether).Found,%: C 60,44; H 9,84; N 7,60; Cl 9,29. C19H37ClN2O3.Calculated,%: C They Accounted For 60,54; H 9,89; N 7,43. Cl 9,40.Example 7. Hydrochloride dicyclohexylamine morpholinoethoxy acid (IV. 7).A mixture of 2.58 g (0.01 mol) of dicyclohexylamine Chloroacetic acid and 4,36 g (0.05 mol) of the research in 25 ml of toluene is boiled for 5 hours the Reaction mass is washed with water, evaporated to dryness. Yield 2.85 g (92,5%), pl. 117-118oC (60% alcohol)
Found,%: C 70,4; 10,48; N 9,11. C18H32N2O2.Calculated,%: C 70,09; H 10,46; N Remaining 9.08.To a solution of 1.5 g of the base in ether is added ether saturated with hydrogen chloride. The precipitate is filtered off. Output hydrochloride IV.7 1.3 g (71,4%). So pl. 260-261oC (decomp.) (from a mixture of acetone with absolute alcohol (3:1).Found,%: Cl 10,30, C18H32ClN2O2.Calculated: Cl 10,28.Example 8. Hydrochloride dicyclohexylamine hexamethyldisiloxane acid (IV.8).A mixture of 2.6 g (0.01 mol) of dicyclohexylamine Chloroacetic acid and 4 g (0.04 mol) of hexamethylenimine in 25 ml of toluene is boiled for 3.5 hours the Reaction mass is then cooled, proliferatum hydrogen to pH 1. The precipitate is filtered off, washed with acetone. Output 2 g (55.8 per cent). So pl. 246-247oC (decomp.) (from isopropyl alcohol).Found,%: C 67,33, H 10,44; N 7,83; Cl 9,84. C20H37ClN2O
Calculated,%: C 67,30; H 10,45; N A 7.85; Cl To 9.93.Example 9. The dihydrochloride of dicyclohexylamine octahedral(1,2-a) prasinococcus acid (IV.9).A mixture of 2.6 g (0.01 mol) of dicyclohexylamine Chloroacetic acid and 2.52 g (0.02 mol) octahedral(1,2-a)pyrazine in 25 ml of toluene is boiled for 3 hours the Reaction mass is then cooled, washed with water and evaporated to dryness. Balance - oil (2.8 g) was dissolved in 20 g of acetone and added ether saturated with hydrogen chloride to pH 1. The precipitate is filtered off, yield 2.3 g (54.7 per cent). So pl. 239-240oC (decomp.) (from isopropyl alcohol).Found,%: C 59,91; H 9,45; N 10,11; Cl Ls 16.80. C21H39Cl2N3O.Calculated,%: C 59,99; H 9,35; N 9,99; Cl 16,86.Example 10. Hydrochloride dicyclohexylamine n-butylaminoethyl acid (IV.10).The mixture 5,16 (0.02 mol) of dicyclohexylamine Chloroacetic acid and 14.6 g (0.2 mol) of n-butylamine is boiled for 6 hours, the Excess butylamine is distilled off, the residue is washed twice with water and extracted with benzene. The benzene solution is washed with water and evaporated to dryness. The residue (m is washed with ether. Yield 4.3 g (65%). So pl. 210-211oC (from isopropyl alcohol).Found,%: C 65,24; H 10,54; N 8,51; Cl 10,66. C18H35ClN2O.Calculated,%: C 65,33; H 10,66; N 8,46; Cl 10,77.Example 11. Hydrochloride dicyclohexylamine ISO-butylaminoethyl acid (IV.11).The mixture 5,16 g (0.02 mol) of dicyclohexylamine Chloroacetic acid and 14.6 g (0.2 mol) of isobutylamine boiled for 6 hours the Reaction mass is evaporated to dryness. Toluene solution is evaporated to half volume and to the residue was added ethyl acetate saturated with hydrogen chloride. Precipitated crystalline precipitate leave for days in the fridge, then filtered off, washed with ether and dried in vacuum at 70oC. Yield 5.6 g (84.7 per cent). So pl. 240-241oC (from isopropyl alcohol).Found,%: C 65,36; H Of 10.72; N 8,33, Cl 10,91. C18H35ClN2O.Calculated,%: C 65,33; H 10,66; N 8,46; Cl 10,71.Example 12. Hydrochloride dicyclohexylamine -(n-butyl)aminopropionic acid (IV.12).The mixture 2,63 g (0,0087 mol) of dicyclohexylamine-bromopropionic acid and 6,36 g (0.1 mol) of n-butylamine boiled for 10 hours, the Reaction mass is evaporated to dryness, the residue is washed with water and extracted with benzene. The benzene solution is washed with water and evaporated dash is washed with ether, dried. Yield 0.6 g (20%). So pl. 265-266oC from isopropyl alcohol).Found,%: C 66,33; H 11,07; Cl 10,61. C19H37ClN2O.Calculated,%: C 66,15; H 10,81; Cl 10,28.Example 13. Hydrochloride dicyclohexylamine cyclohexasiloxane acid (IV.13).The mixture to 2.57 g (0.01 mol) of dicyclohexylamine Chloroacetic acid and 10 ml of cyclohexylamine boiled for 5 hours, the Excess cyclohexylamine evaporated. The residue is dissolved in 25 ml of acetone, add concentrated hydrochloric acid to pH 1, leave to stand overnight. The precipitate is filtered off. Output, 2.2 g (61,6%). So pl. 242-243oC (decomp.) (from isopropyl alcohol).Found,%: C 67,19; H 10,50; N Of 7.90; Cl 9,90. C20H37ClN2O.Calculated,%: C 67,29; H 10,45; N A 7.85; Cl To 9.93.Example 14. The dihydrochloride of dicyclohexylamine-amino-ethyl)aminouksusnoy acid, hydrate (IV.15).A mixture of 2.58 g (0.01 mol) of dicyclohexylamine Chloroacetic acid and 3 g (0.5 mol) of 88% ethylene diamine in 25 ml of ethanol is boiled for 11 hours the Reaction mass is evaporated to dryness. The residue is alkalinized with concentrated aqueous ammonia solution and extracted with benzene. The benzene solution is washed with water and evaporated to dryness. The residue is dissolved in ether and added ether, saturated with the alcohol and with ether).Found,%: C 51,61; H 9,39; N 11,42; Cl 18,86. C16H35Cl2N3O2.Calculated,%: C 51,60; H For 9.47; N 11,28; Cl 19,04.Example 15. Hydrochloride dicyclohexylamine aminouksusnoy acid hydrate (IV.4).To a solution of 2.58 g (0.01 mol) of dicyclohexylamine Chloroacetic acid in 25 ml of alcohol was added saturated aqueous ammonia to pH 10-12 (10 ml) and left to stand at 20oC for 2-3 weeks. The reaction mass was added water, a small amount of 25% aqueous ammonia solution and the mixture extracted with ether. The ether solution is washed with water and evaporated to dryness. The residue is dissolved in ether and added ether saturated with hydrogen chloride to pH 1. The precipitate is filtered off, washed with ether. Yield 1.7 g (58%). So pl. 229-230oC (from a mixture of alcohol and ether).Found,%: C 57,24; H 9,83; N 9,48; Cl 11,95; C14H29ClN2O2.Calculated,%: C 57,42; H 9,98; N To 9.57; Cl 12,11.Pharmacological results obtained in the study of dicyclohexylamine N-substituted - amino acids.Were conducted pharmacological study of the compounds of General formula IV, which are soluble in water, physiological solution and therefore comfortable for intravenous and intraperitoneal introduction yarnie number of compounds of General formula I and IV showed the same pharmacological effect, therefore, in the tables give the results of studies of the compounds of General formula IV, which are more convenient for experimental work.Pharmacological study of the inventive compounds of General formula IV is first carried out using complex methods used for primary evaluation of the antiarrhythmic effect, taking into account the correlation between chemical structure-new compounds and their anti-arrhythmic activity. To this end used acontinuous and chloralkali model arrhythmias.Effective dose (ED50) and lethal dose (LD50) and their confidence limits were calculated by the method of Miller and Tainter (10) at the confidence level p= 0.05. The experiments were carried out on outbred white rats weighing 180-200 g intravenously claimed compounds. As a criterion of therapeutic breadth of the claimed compounds used against a lethal dose (LD50) to median effective dose (ED50)-LD50ED50that meant as an antiarrhythmic index . Range of the antiarrhythmic activity of the most promising compounds were investigated in future models of the heart rhythm with the determination of the threshold electric atrial ventricle in to the 8], and also model two-stage ligation of the coronary artery in dogs according to the method of Harris  to identify properties characteristic of antiaritmikov I class.Thus, for the studies used a range of methods experimental play in awake and shot animals, allowing to detect anti-arrhythmic properties of the claimed compounds.Table 1 presents the results of a study of anti-arrhythmic properties of the inventive compounds on chloralkali model arrhythmia. Experiments were performed on awake outbred rats weighing 180-200 g calcium Chloride was administered in the form of a 10% solution at a dose of 200-250 mg/kg In the beginning selected for each weight of the animal, the dose of calcium chloride, causing death from occurring within 1-1,5 min of ventricular fibrillation, then the compounds were administered over 1-3 min before the introduction of calcium chloride. ECG was recorded in the second standard lead on the appliance ALCAR-2. Antiarrhythmic effect was assessed by the reduction in the incidence of lethal ventricular fibrillation. The obtained data were processed by the method of Litchfield .The studied compounds on the antiarrhythmic activity on the model chloralkali the BR> Continuou fibrillation evoked in awake rats weighing 180-200 g, entering into the tail vein of the solution aconitine at a dose of 30-40 mg/kg there was rhythm mixed atrioventricular character that represents a usually politono extrasystoles. The claimed compounds were injected intravenously for 1-3 min before the introduction of aconitine.As can be seen from table 2, most of the claimed compounds have proven to be very effective in preventing arrhythmias in this model, significantly outperforming the drugs of class I antiarrhythmic action lidocaine, handin and procainamide taken for comparison as reference drugs. In accordance with the average effective dose of a compound can be placed in the following sequence in descending order antiarrhythmic activity:
To identify antifibrillatory activity of compounds IV.1; IV.10 studied their influence on the threshold of the electrical ventricular fibrillation caused by electric stimulation.This method gives the opportunity to compare antifibrillatory properties of the compounds of importance in connection with the need to prevent the occurrence of ventricular fibrillation due to EOI death.Experiments were performed on cats weighing 2-3 kg, shot with Nembutal (35 mg/kg) during artificial respiration. After opening the chest and pericardium on the left ventricular myocardium was applied to the platinum electrodes. Electric irritation from 3-channel electronic stimulator SEN-7201 (Nihon Kohden, Japan) was created ectopic excitation focus". Heart rhythm disturbances (ventricular fibrillation) was caused by a series of rectangular pulses of increasing intensity (20 pulses per bundle), the duration of each 4 MS and a repetition rate of 50 Hz. Over the threshold of ventricular fibrillation took the minimum number of mA irritating current, causing fibrillation. When recorded on the EKG and drop in blood pressure. Blood pressure in the femoral artery were recorded using electromanometer Elema, Sweden). ECG was recorded in the second standard lead on the electrocardiograph ALCAR-2 and the coordinate recorder analyzer Task-350 (Nihon Kohden, Japan), simultaneously with the recording pulse pressure.The study drugs were injected into the femoral vein in 10 ml of physiological solution for 3 minutes Used doses of 4.5 and 8 mg/kg for lidocaine and 2 and 5 mg/kg of quinidine.go directly to the myocardium from the defibrillator DI-03.As can be seen from the results shown in table 3, the studied compounds IV. 1; IV.10 have strong antifibrillatory properties. They raise the threshold a more intense and prolonged than the comparison drug lidocaine, almost the only drug widely used in the clinic for the treatment of life-threatening arrhythmias in post-mi patients and for the prevention of sudden death.Ventricular arrhythmias caused by occlusion of the descending branch of the left coronary artery, get in awake dogs, operated by the method of Harris (1950). The experience of many pharmacological laboratories of the world shows that compounds that demonstrate activity in this model has proven effective in the clinic and reveal the antiarrhythmic properties of class I suppressing fraction constant level of sodium currents at depolarized ischemia myocardial cells.Experiments put on dogs weighing 8 to 15 kg Animals were anestesiologi with Nembutal (35 mg/kg intravenously) after intubation were placed on artificial respiration, were fixed on the operating table in position on the right side. Aseptically opened the chest in the fourth intercostal space to the left. The pericardium the abuse the AI were applied injection needle N20. The first ligature was tied on the needle that was created after removal of the needle decreases the circulation of blood in the underlying area of the myocardium. The second ligature was tied tightly over 30 minutes after the first. The wound in layers sewn, administered antibiotics. During the operation produced a recording of ECG in the second standard lead, made a permanent video surveillance. In the jugular vein was implanted polyethylene catheter filled with heparin, the catheters were led subcutaneously to the neck in the neck. After 24 h in the experience took only animals that are in satisfactory condition and had sustained ventricular arrhythmias. The analyte was injected slowly into the jugular vein in 10 ml of physiological solution.The effectiveness of the substances was evaluated by their ability to restore normal sinus rhythm, as well as the degree of decrease in the frequency of ectopic excitation of the ventricles. When the statistical processing of the results was used t-test t-test.Investigated the influence of the most active of previously identified compounds IV. 1 at doses of 3.3 and 8 mg/kg and IV.10 at doses of 3.3, 5.0, and 6.6 mg/kg when administered intravenously in 10 ml of physiological solution. The effectiveness of compounds of this model against the accepted reduction in cumulative reductions of 50% or more.A total of 27 experiments in this series. Intravenous connection IV. 10 in a dose of 5 mg/kg already in the 1st minute of the action ectopic reduction eliminated, and the total number of heart contractions is reduced by 30%. As can be seen in Fig. 1, persistent anti-arrhythmic effect is maintained for more than 30 min (bottom graphs). 45 minute percentage of ectopic contractions back to the original. Lidocaine in equimolar dose of much inferior in activity to compound IV.10. At this dose, this connection reduces the total number of heartbeats in an average 6% and duration of suppression of ectopic contractions is more than 30 minutes duration of the effect of lidocaine was no more than 15 minutesCompound IV.1 at a dose of 3.3 mg/kg in 5 min after intravenous injection reduced the total number of heart contractions by 13% and the number of ectopic contractions on 30-8%. A greater dose of 8 mg/kg and this connection reduces the total number of heart contractions by 13%, and ectopic excitation of the ventricles on 42-100%, while lidocaine dose in this reduces the total number of heart contractions by 8%, and ectopic 70%. The duration of the antiarrhythmic effect of 30 minutes As shown in Fig. 2, compound IV.1 (avici - the dotted line).Thus, the most active compound IV.1 and IV.10 have strong anti-arrhythmic properties I "In" class.As you know, arrhythmogenic effect BaCl associated with a decrease in potassium conductance, so hloridnaja model arrhythmia is considered adequate for the emergence of properties of class III antiarrhythmic actions.Experiments were performed on conscious rabbits of both sexes weighing 2-4 kg according to the method described by L. Szektres and Gy.J. Papp (1971). Rabbits were injected with 4 mg/kg BaCl in the marginal ear vein in the form of 2% solution for 1 min In response to intravenous administration of a solution of BaCl after a latent period of a few seconds have heart rhythm disturbances in the form of polytopes ventricular arrythmia, which continue until 30 minutesECG was recorded in the second standard lead every minute for 15 minutes. The ECG recording were made every minute for 12 C. In subsequent experiments took those rabbits who have every minute for 15 min was at least one of the beats.As BaCl is a very toxic substance and is excreted slowly, then selected in the control experiments, rabbits stood before Accademia BaCl solution for 1-th and 2-th minute, and then were administered the test substance in the form of a 1% solution for 30 s was Recorded ECG at each minute for 15 minutesThe effect of the compounds was assessed by the ability to restore normal sinus rhythm within 1 or more minutes. In each rabbit, selected in control, looked 3-5 doses connection with an interval of 3-4 days.The antiaritmikom class III sematilide, taken as a reference, at a dose of 2.5-5.0 mg/kg eliminated arrhythmia caused by the intravenous injection of barium chloride. The most active of the claimed compounds IV.10 was effective in a dose range 0,125-0,25 mg/kg, indicating that it has a significantly higher efficiency in this model. Dicyclohexylamine N-substituted-aminocarbonyl acids of General formula
< / BR>where R1is hydrogen or lower alkyl;
R2and R3- same or different and mean hydrogen, lower alkyl, hydroxy(lower alkyl), aminoethyl, cyclohexyl, or R2and R3along with carrying their nitrogen atom form a saturated 6 - or 7-membered heterocycle, which can contain an additional nitrogen atom or oxygen, or mean piperazine where the nitrogen atom in the 4-th position and the neighboring atom coal what if their Quaternary salts.
< / BR>where R1- represents a group of formula
< / BR>where n = 1 or 2, R3represents hydroxyl, lower alkoxygroup, aryl (lower) alkoxygroup, amino group, lower alkylamino or di (lower alkyl) amino group, R4represents hydrogen, lower alkyl or aryl (lower) alkyl , R5represents hydrogen, lower alkyl, aryl (lower) alkyl or lower alkylsulphonyl, R6represents hydrogen or lower alkyl, provided that when R6is lower alkyl, then R6replaces one of the methylene hydrogen atoms, R2represents a group of formula
< / BR>where X is hydrogen, halogen, lower alkyl or lower alkoxygroup,
R7represents lower alkyl or aryl (lower) alkyl,
R8represents hydrogen or lower alkyl,
R9represents hydrogen, lower alkyl, lower alkenyl, lower quinil, aryl (lower) alkyl, formyl, lower alkyl carbonyl, aryl (lower alkyl) carbonyl Il is kilcarbery,
R11represents hydrogen, lower alkyl or aryl (lower) alkyl,
and such compounds are applicable for alleviating various memory disorders, characterized by a cholinergic deficit such as disease Alzheimer
FIELD: chemistry; pharmaceutics.
SUBSTANCE: present invention relates to a solid pharmaceutical composition for treating malignant tumours, including malignant tumours in the larynx, thyroid gland, perspiratory glands, kidneys, prostate gland, Hodgkin's disease, non-Hodgkin's lymphoma and leucosis, containing an effective amount of the crystalline form of suberoylanilide hydroxamic acid (SAHA), obtained through a method which involves recystallisation of an unrefined SAHA preparation from a mixture of methanol and water in ratio of approximately 2:1, and a carrier.
EFFECT: obtaining a solid pharmaceutical composition for treating malignant tumours.
9 cl, 20 tbl, 14 dwg, 7 ex
SUBSTANCE: invention relates to a method of producing γ-amides of glutamic acid of formula , where R4 is an amino-protective group selected from a carbobenzyloxy group (CBz), R5 is a straight or branched C1-C10alkyl, R2 and R3 independently represent a hydrogen atom, R-NH2 is a 3-amino-derivative of bile acid, which are further capable of reacting to form valuable organic compounds - ligands, complexes with ions of paramagnetic di-tri-valent metals selected from a group consisting of Fe(2+) Fe(3+), Cu(2+), Cr(3+), Gd(3+), Eu(3+), Dy(3+), Yb(3+) or Mn(2+) of which can serve as a base for preparing diagnostic compositions for use in NMR-tomography of the blood circulatory system of humans and animals.
EFFECT: design of an efficient method of producing γ-amides of glutamic acid.
1 cl, 20 ex
SUBSTANCE: invention relates to 2'-bromanilide-3-N,N-diethylaminopropanoic acid nitrate (I)
and 2'-bromanilide-3-N,N,N-triethylaminopropanoic acid iodide (II)
having antiarythmic activity.
EFFECT: compounds have antiarythmic activity which surpasses that of lidocaine with virtually the same toxicity.
1 tbl, 1 ex
SUBSTANCE: in formula I Rf is an alkyl group containing 1-2 carbon atoms, in which 1-5 hydrogen atoms are substituted with 1-5 fluorine atoms, and R is an amine group or an amine group substituted with an amino acid residue of general formula NH(COCHR'NH)-H, where R' is hydrogen, a side chain of natural amino acid which is C1-C4alkyl, possibly substituted with a hydroxy group, a hydroxyl group, disodium or an ammonium phosphate group. The invention also relates to versions of the method of producing compounds of formula I, involving the following steps: fluoroalkylation of 4-hydroxy-3-methoxybenzaldehyde or 4-hydroxybenzaldehyde in the presence of an interphase transfer catalyst, to obtain 4-fluoroalkoxy-3-methoxybenzaldehyde (V) or 4-fluoroalkoxybenzaldehyde (VII), respectively, subsequent selective demethylation (V) with lithium diphenylphosphine and a protection of a hydroxy group or nitration (VII) in the 3rd position. The obtained compounds undergo Wittig reacton using a ylide of 3,4,5-trimethoxybenzyltriphenylphosphonium and the desired product is extracted.
EFFECT: obtaining novel combretastin derivatives of formula (I), having angiogenesis inhibiting activity, which can be used as anticancer and/or antiangiogenic agents.
6 cl, 17 ex, 4 dwg
SUBSTANCE: invention relates to methods of producing compounds of formula iii and an optically enriched salt of the compound of formula iii, where R1 is C1-C6 alkyl; R'1 is hydrogen; R'2 is -NHR2; R2 is C3-C6 cycloalkyl. The methods are realised by oxidising an unsaturated compound of formula i , where the oxidant is tert-butylhydroperoxide, a mixture of samarium (III) isopropoxide, triphenyl arsine oxide, S-(-)1,1'-bi-2-naphthol and 4 Ǻ molecular sieves, or urea-hydrogen peroxide in the presence of trifluoroacetic anhydride to obtain a compound of formula ii ; and further reaction of the compound of formula ii with an amination agent, where the amination agent is an azide salt, and the intermediate azide-compound is reduced by hydrogenation to obtain a compound of formula iii. By reacting the compound of formula iii with an optically active organic acid selected from L-tartaric acid, malic acid, diisopropylidene gulonic acid and deoxycholic acid in a solvent, a salt of the compound of formula iii is obtained; and said salt is crystallised to obtain the same salt with more than 55% enantiomeric excess. The invention also relates to compounds: N-cyclopropyl-3-propyloxirane-2-carboxamide; 3-azido-N-cyclopropyl-2-hydroxyhexanamide; 3-amino-N-cyclopropyl-2-hydroxyhexanamide, salt of L-tartaric acid; 3-amino-N-cyclopropyl-2-hydroxyhexanamide, salt of deoxycholic acid.
EFFECT: improved methods of producing compounds of formula iii and an optically enriched salt of a compound of formula iii, novel intermediate compounds for producing serine protease inhibitors.
29 cl, 2 dwg, 14 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: device refers to new styrene derivatives with the structure formula A in the form of geometrical isomers or tautomers and their pharmaceutical acceptable salts. In structural formula (A) R1 represents hydrogen; R2 represents hydrogen or C1-C6alkyl; R3, R4, R5 and R6 are identical or different and independently represent hydrogen, halogen, C1-C6alkyl or -OR12; R7 represents hydrogen or C1-C6alkyl; R8 represents hydrogen; R9 represents hydrogen, C1-C6alkyl, or -C(=O)R13; R10 represents hydrogen or C1-C6alkyl; Z represents W-Y, wherein W represents -C(R14)(R15)-; Y represents -C(R16)(R17)-; each R12 independently represents hydrogen or C1-C6alkyl; each R13 independently represents C1-C6alkyl; R14 and R15 are identical or different, and independently specified in hydrogen, fluoro, methyl, ethyl, trifluoromethyl, -OH, -OCH3 or -NH2; or R14 and R15 together form oxo; R16 and R17 are identical or different and independently represent hydrogen, halogen, C1-C6alkyl or -OR12. The other radical values are specified in the patent claim.
EFFECT: compounds may be used for treating an ophthalmic disease or disorder in an individual which can represent age-related macular degeneration or Stargardt macular degeneration.
17 cl, 14 tbl, 143 ex
SUBSTANCE: in formula (I) R1 and R2 each represents a hydrogen atom, formula -(CR4R4')-O-CO-R5, or -(CR6R6')-O-CO-OR7, or formula (IIa) or (IIb), R3 represents a hydrogen atom, formula -(AA)n-H, -CO-O-(CR9R9')-O-CO-R10, or -CO-O-(CR9R9')-O-CO-OR11, or formula (III), R4 and R4' each represents a hydrogen atom or a C1-6alkyl group, R5 is a C1-10alkyl, adamantyl or phenyl group, R6 and R6'each represents a hydrogen atom or C1-6alkyl group, R7 is a C1-10alkyl, C3-8cycloalkyl or adamantyl group, R8 is a C1-6alkyl group, R9 and R9' each represents a hydrogen atom or C1-6alkyl group, R10 is a C1-10alkyl group, R11 is a C3-8cycloalkyl group, R12 is a C1-6alkyl group, AA is an aminoacyl group and n is an integer from 1 to 3.
EFFECT: application of compounds for prevention or treatment of the diseases listed above.
17 cl, 7 tbl, 42 ex