The hydrochloride of n-(beta-hydroxyethyl)tsitizina showing antiarrhythmic activity
(57) Abstract:The invention relates to pharmaceutical industry and relates to new compounds of the hydrochloride of N-(-hydroxyethyl)tsitizina formula (I) exhibiting high antiarrhythmic activity and low toxicity. 1 PL.The invention relates to new biologically active chemical compound, specifically to the hydrochloride of N-(-hydroxyethyl)tsitizina (I), formulashowing antiarrhythmic activity. The specified connection and its properties are not described in literature.Currently in clinical practice in the treatment of various arrhythmias have found an extensive use drugs such as quinidine, procainamide, aymalin, ritilin, lidocaine, etmozin etc. However, these tools have a number of disadvantages, namely: low anti-arrhythmic activity in the various forms of arrhythmia, a relatively high toxicity, the presence of hypotensive and negative inotropic action, short duration antiarrhythmic effect . The most important for drug, possess antiarrhythmic activity, is the breadth of his those used antiarrhythmic drugs have serious disadvantages. Therefore, the search of antiaritmikov remains an urgent task.The closest properties to the proposed connection is VFS, clinical study which showed that he is a highly effective antiarrhythmic agent for various forms of arrhythmias and is especially effective in various forms of ventricular arrhythmias, proximale atrial fibrillation and chronic monotonously atrial tachycardia [2-4].However, despite the high antiarrhythmic index allapinina active substance which is diterpenoid alkaloid lappaconitine, its high toxicity does not allow the clinic to show all its advantages over existing drugs similar type of action.The task, which directed the claimed technical solution is to search for new compounds with high anti-arrhythmic activity in the various forms of arrhythmia.In the claimed technical solution synthesized a new molecule hydrochloride N-(-hydroxyethyl)tsitizina (I) exhibiting anti-arrhythmic activity.Acute toxicity of the compound (I) was determined on the white bespar the tion (I) is a low-toxic substance. The research results are summarized in the table.Antiarrhythmic properties of compound (I) was studied on aconitine and chloride-calcium models of cardiac arrhythmia. As Comparators used VFS and the number of known antiarrhythmic drugs. Studies have shown that the compound (I) has a high antiarrhythmic activity models, reproducing various cardiac arrhythmias, including the most life-threatening - fibrillation. The research results are summarized in the table. The compound (I) exhibits a pronounced efficiency on both models arrhythmia and has the greatest antiarrhythmic index among the known antiarrhythmic drugs (the ratio of lethal dose to effective LD50/ED50). The hydrochloride of N-(-hydroxyethyl)tsitizina (I) according to the intensity of anti-arrhythmic action and good endurance surpasses most of the known antiarrhythmic drugs, 250 times less toxic than VFS (see table).The compound (I) was obtained by treatment of 5% aqueous solution of hydrochloric acid N-(-hydroxyethyl)tsitizina obtained by the interaction tsitizina with ethylene oxide.Thus, the proposed new small is encompassed in the treatment of various forms of arrhythmias.The invention is illustrated by the following examples.Example 1. Synthesis of compound (I)1a. Synthesis of N-(-hydroxyethyl)tsitizina. To a solution of 1.0 g (5.3 mmol) tsitizina in 10 ml of methanol was added 0.3 g (8 mmol) of ethylene oxide. The reaction mass was kept for 3 days at a temperature of 0-5C. The solvent was distilled under vacuum, and the residue was recrystallized from methanol. Received 1.2 g (96%) N-(-hydroxyethyl)tsitizina, so pl. S. Found (percent): C, 66,71; N, The 7.65; N, 11,83; C13H18N2O2. Calculated (%): C, 66,64; N 7,74; N, 11,96. An NMR spectrum1H (CDCl3, , M. D.): 1,25 (OH); 1,82 d and was 1.94 (2HandFrom(11) and(13), J=12,85 Hz); 2,40-2,60 m (1H-C(9) 2N-C(8), 2HeFrom(11) and(13)); 3,00 t (2H-NH2, J=9,77 Hz); 3,50 t (2N-CH2O, J=5,34 Hz); a 3.87-3,93 D. D. (1HeFrom(10), J=8.30 and 7,44 Hz); 4,10 (1Ha-C(10), J=15,51 Hz); 6,00 d (1H-(5), J=6.75 Hz); 6,45 d (1H-C(3), J=9,07 Hz); 7.25 and 7,30 D. D. (1H-C(4), J=7,37-remaining 9.08 Hz). An NMR spectrum13With (, m D.): 25,40 t ((8)); 28,56 d ((9)); 34,97 d ((7)); 49,63 t ((10)); 57,67 t ((15)); 58,76 t ((11)); 59,76 t ((14)); 59,64 t ((13)); 104,67 d ((3)); 138,57 d (C(4)); 150,87 with (With(6)); 163,12 with (s(2)).1B. Synthesis of hydrochloride of N-(-hydroxyethyl)tsitizina. To a solution of 1.0 g (4.3 mmole) N-(-hydroxyethyl)tsitizina in 10 ml of methanol was pricipally to the acid reaction of a 5% aqueous solution of Hcl. The solvent was distilled in vacuum, the residue Perekrest the UB>O2Cl. Calculated (%): C, 57,67; N 7,07; N, 10,35; Cl To 13.09. IR-spectrum /cm-1: 3600 (OH); 1644 (C-O); 636 (CH=CH). An NMR spectrum1N (D2O , M. D.): 1,90 (ush.S., 1 H, H2With(8)); 2,41-2,62 (m, 5 H, HC(9), N2WITH(11), N2With(13)); to 3.02 (t, 2 H, H2With(14), J=13,5); 3,22 (ush.S., 1 H, HC(7)); 3,63 (t, 2 H, H2With-IT, J=6,0); 3,90-of 4.05 (m, 2 H, H2With(10); 6,45-to 6.57 (m, 2 H, HC(3), HC(5)); to 7.61 (t, NS(4), J=7,9). An NMR spectrum13With (, m D.): 26,61 t ((8)); 29,16 d ((9)); 37,07 d ((7)); 52,60 t ((10)); 60,14 t ((15)); 61,38 t ((11)); 62,19 t ((14)); 62,20 t ((13)); 111,02 d ((3)); 143,25 d (C(4)); additional 154.36 (C(6)); 166,94 with (s(2)).Example 2. Determination of acute toxicityAcute toxicity hydrochloride N-(-hydroxyethyl)tsitizina was determined in anesthetized rats weighing 150-160 g according to the Litchfield-Wilcoxon signed with intravenous awake animals . For the behavior and condition of the animals was observed within 24 h after drug administration. Lethal dose (LD50) this connection is 1500 mg/kg Studies have shown that the studied compound (I) is low toxic substance.Example 3. The study of the antiarrhythmic activity of the hydrochloride of N-(-hydroxyethyl)tsitizina on aconitine model fibrillationContinua model arrhythmia allows to study the influence of connections on a mixed form naru is Mostovoy vein at a dose of 50 mcg/kg anesthetized rats weighing 150-160 g Under the influence of aconitine after 1-3 min occurs polytopia premature beats, ventricular tachycardia and fibrillation, which can be associated with arrhythmia observed in clinical conditions. Registered arrhythmias atrioventricular type Compound (I) was administered prophylactically for 1-2 min before the introduction of aconitine. The electrocardiogram (ECG) were recorded in II standard lead 3, 5, 10, 15, 20, etc. minutes within 2 hours the activity of the compounds was assessed by its ability to prevent the development of cardiac arrhythmias under the influence of aconitine.The compound (I) contributed to a more rapid recovery arrhythmia mixed type with the introduction of aconitine, reducing the duration of the arrhythmia at 30±4,2 min compared with the control. Effective dose (ED50) the compound (I) intravenously on aconitine model arrhythmia equal to 0.25 mg/kg of the studies are summarized in the table.Example 4. The study of the antiarrhythmic activity of the hydrochloride of N-(-hydroxyethyl)tsitizina on chloralkali model fibrillationChloralkali (ventricular) arrhythmias caused nonlinear anesthetized rats weighing 150-160 g introduction into the tail vein of 250 mg/kg chlorine is aciu ventricular 1-2 minutes Some animals ventricular extrasystoles in combination with sinus bradycardia and block atrioventricular holding gave way to the emergence of short periods of ventricular tachycardia. The analyzed compound (I) was administered intravenously over 2 min before the introduction of aritmogeni. The electrocardiogram (ECG) were recorded in II standard lead. The criterion antiarrhythmic effect took the decrease in the percentage of fatal cases of atrial and percentage of prevention are studying the connection of the death of the animals. The effective dose of compound (I) (U50) was determined by the Litchfield-Wilcoxon signed.On chloralkali fibrillation study the compound (I) at a dose of 0.14 mg/kg completely prevented the death of animals. This substance contributed to the reduced incidence of atrial induced lethal dose l2. The research results are summarized in the table.The compound (I) contributed to a more rapid recovery arrhythmia mixed type with the introduction of aconitine, reduction of fatal cases of atrial caused by the introduction of high doses of calcium chloride. Thus, the hydrochloride of N-(-hydroxyethyl)tsitizina has a pronounced antiarrhythmic effect, prevastatin.-1986.2. Kurbanov R. D., Abdullayev T. A. Pharmacodynamics and efficacy allapinina in patients with abnormal heart rhythm // Clinical medicine, 1988.- So 66.- No. 10.- S. 52-55.3. Setnew A. S. Golitsyn, S. P., Levin, E. 3. A comparative study of antiarrhythmic efficacy allapinina, atalina and mexitil in patients with ventricular arrhythmias // Ter. arch.1988 at M.V.Lomonosov.- So 60.- No. 8.- S. 34-38.4. Gasilin C. S. Dorofeev, E. C., N. Rozov.And. The experience of prolonged use allapinina in outpatient practice, Cardiology, 1990.- So 30.- No. 9.- C. 30-32.5. Belenky, M. L. elements of a quantitative evaluation of the pharmacological effect. L., Medgiz.-1963.-S. 152. The hydrochloride of N-(-hydroxyethyl)tsitizina formulashowing antiarrhythmic activity.
< / BR>where t is 1; a and b each represent H; R1represents aryl, optionally substituted by one or more groups selected from lower alkyl, lower alkoxy, nitro, trifloromethyl, triptoreline; aromatic 5-membered monocyclic system which consists of carbon atoms and contains sulfur as one heteroatom; a saturated 5-membered monocyclic system which consists of carbon atoms and contains nitrogen as one heteroatom, which is optionally substituted by aralkyl, and aryl optionally substituted with halogen; provided that when R1represents optionally substituted aryl, R1is not dialkoxybenzene; Y2represents (CH2)qwhere q is 0; X2is SO2; R3represents H, lower alkyl, in which one hydrogen atom substituted aromatic 6-membered monocyclic system which consists of atom N; R2represents aryl, optionally substituted by one or more groups selected from lower alkyl, lower alkoxy, nitro, trifloromethyl, triptoreline; aromatic 5-membered monocyclic system which consists of carbon atoms and contains sulfur as one heteroatom; a saturated 5-membered monocyclic system which consists of carbon atoms and contains nitrogen as one heteroatom, which is optionally substituted by aralkyl, and aryl optionally substituted with halogen; Y1represents (CH2)pwhere p is 1; NS=SN or ethinyl; X1is C=O or (CH2)nwhere n is 0, 1 or 2; R4represents H, lower alkyl, in which one hydrogen atom substituted aromatic 6-membered monocyclic system which consists of carbon atoms and contains nitrogen as heteroatom
< / BR>where R(2) and R(3) independently from each other denote hydrogen, Cl, Br, J, (C1-C8)-alkyl, (C3-C8-cycloalkyl or(5), R(5) - (C1-C8)-alkyl, and one of the two substituents R(2) and R(3) is always hydrogen, however, both Deputy R(2) and R(3) at the same time are not hydrogens, as well as their pharmaceutically acceptable salts
< / BR>where n is 0 or 1;
m is 0 or 1;
p is 0;
X represents oxygen or sulfur;
Y represents CH, N or NO;
W represents oxygen or H2;
And represents N or C(R2);
G represents N or C(R3);
D represents N or C(R4)
provided that not more than one of A, G and D represents nitrogen, but at least one of Y, a, G, and D represents nitrogen or NO;
R1represents hydrogen or C1-C4-alkyl;
R2, R3and R4are independently hydrogen, halogen, C1-C4-alkyl, C2-C4alkenyl,2-C4-quinil, aryl, heteroaryl, including five - or six-membered aromatic ring with 1 or 2 nitrogen atoms, as well as furyl or morpholyl, HE OS1-C4-alkyl, CO2R1, -CN, -NO2, -NR5R6or R2and R3or R3and R4accordingly, together with part a and G or G and D southwest a hydrogen, WITH1-C4-alkyl, C(O)R7C(O)OTHER8WITH(O)OR9, SO2R10, -NR5R6, (CH3)3Si and phenyl, or may together represent (CH2)jQ(CH2)kwhere Q represents a bond; j is 2 and k is 0 to 2;
R7, R8, R9, R10and R11are independently C1-C4-alkyl, NH2, aryl or its enantiomer,
and their pharmaceutically acceptable salts, and methods for their preparation, intermediate compounds and pharmaceutical compositions, which has an activating effect against nicotine7-acetylcholine receptors and can be used for the treatment and prevention of psychotic disorders and disorders of the type of lower intellectual
FIELD: organic chemistry, chemical technology, medicine.
SUBSTANCE: invention relates to new biarylcarboxamides of the general formula (I): wherein A means compound of the formula (II): ; D means oxygen atom (O) or sulfur atom (S); E means a simple bond, oxygen atom, sulfur atom or NH; Ar1 means 5-membered heteroaromatic ring comprising one nitrogen atom (N) and one sulfur atom (S) or one oxygen atom (O), or one S atom, or one N atom; or 6-membered aromatic ring, or heteroaromatic ring comprising one N atom; Ar2 means 5-membered heteroaromatic ring comprising one S atom or on O atom, or one N atom and one O atom, or one N atom; or 6-membered aromatic ring or heteroaromatic ring comprising one N atom; or 9-membered condensed heteroaromatic ring system comprising one O atom, or 10-membered condensed aromatic ring system, or heteroaromatic ring system comprising one N atom wherein aromatic ring Ar2 is possibly substituted with one or two substitutes taken among halogen atom, (C1-C4)-alkyl, cyano-group (-CN), nitro group (-NO2), NR1R2, OR3, trihalogen-(C1-C4)-alkyl, (C1-C4)-acylamino-, hydroxy-, morpholino-, amino-, methylamino-group, amino-(C1-C4)-alkyl and hydroxymethyl but if Ar1-phenyl and Ar2 represent quinolinyl group then Ar2 is substituted with one or two (C1-C4)-alkyls, -CN, -NO2, NR1R2, OR3 wherein R1, R2 and R3 mean (C1-C4)-alkyl and compound of the formula (III) doesn't represent .
EFFECT: improved preparing and treatment methods.
33 cl, 69 ex
FIELD: organic chemistry, chemical technology, medicine, pharmacy.
SUBSTANCE: invention relates to novel derivatives of quinuclidine of the general formula (I):
wherein © represents phenyl ring, (C4-C9)-heteroaromatic group comprising one or some heteroatoms, naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl or biphenyl group; R1, R2 and R3 represent hydrogen halogen atom, phenyl and others; n represents a whole number from 0 to 4; A represents group -CH=CR6-, -CR6=CH-, -CR6R7 and others; R6 and R7 represent hydrogen atom, alkyl and others; m represents a whole number from 0 to 8; p represents a whole number from 1 to 2; and a substitute in azoniabicyclic ring can be at position 2, 3 or 4 including all possible configurations of asymmetric carbon atoms; B represents the group of the formula i) or ii) wherein R10 represents hydrogen atom, hydroxyl group or methyl; each R8 and R9 represents: wherein R11 represents hydrogen, halogen atom, alkyl; Q represents a single bond, -CH2- and others; X represents pharmaceutically acceptable anion of mono- or polyvalent acid. Compounds of the formula (I) possess antagonistic activity with respect to muscarinic M3-receptors and can be used in medicine for treatment of diseases wherein muscarinic M3-receptors are implicated.
EFFECT: improved preparing method, valuable medicinal properties of compounds.
36 cl, 164 ex
FIELD: medicine, dermatology.
SUBSTANCE: one should treat eruptive area with a gaseous flow of plasmochemical nitrogen oxide by replacing the flow along concentric trajectory against perifocal area towards ulcerous center, from the distance of 25 cm at the phase of exudative process 5 times weekly and from the distance of 15 cm during active proliferation thrice weekly at exposure time being 10 sec/sq.cm at the background of ciprolet, detralex, phencarol and aevit intake. The present innovation enables to decrease side effects due to deteriorating inflammatory processes, improving microcirculation, skin barrier function and regenerative processes.
EFFECT: higher efficiency of therapy.