N-1-[(4-fluorophenyl)-2-(1-ethyl-4-piperidyl)-ethyl]-4-nitrobenzamide hydrochloride exhibiting antiarhythmic and antifibrillatory activity
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to a new chemical compound - N-1-[(4-fluorophenyl)-2-(1-ethyl-4-piperidyl)-ethyl]-4-nitrobenzamide hydrochloride of formula Also, the invention refers to drugs.
EFFECT: preparation of a new biologically active compound which exhibits antiarhythmic and antifibrillatory activity.
2 cl, 1 ex, 2 tbl
The invention relates to new chemical compound is the hydrochloride of N-1-[(4-forfinal)-2-(1-ethyl-4-piperidyl)-ethyl]-4-nitrobenzamide formula
which shows antiarrhythmic and antifibrillatory activity and can be used in medicine. The specified connection and its properties are not described in literature.
In the late 80-ies began an active search for effective drugs belonging to the group of anti-arrhythmic drugs class III due to the advent of the first conclusive evidence of a potential risk of developing life-threatening side arrhythmogenic effects when using widely used then worldwide drugs class I . Such antiaritmiki as enkainid, flecainide, quinidine, and others were highly effective in the treatment of cardiac arrhythmias, including atrial fibrillation (AF), however, their use in persons with organic lesions of the heart, especially myocardial infarction, not only does not decrease, but may increase the mortality of patients with ventricular and supraventricular arrhythmias .
A particular problem is an antiarrhythmic treatment of patients with AF, which is the most common type of heart rhythm disturbance. Epidemiological data indicate the presence of MA at an average of 0.5% of the people, to whom I patients increases with age up to 6-7% at 80 years . The danger of MA is associated with a high risk of disability and death due to ischemic stroke, the frequency of which is several times higher than in comparable age groups without MA .
The lack of effective and safe antiarrhythmic drugs gave rise to numerous studies in the 90-ies, which have been synthesized and are being actively studied III antiarrhythmic agent of class dofetilide, sematilide, ibutilide, azimilide and many others [5-8]. However, significant success has been achieved due to difficulty of synthesis of drugs selective actions that would avoid specific to class III serious prioritiesin side effects in the form of polymorphic ventricular tachycardia.
In the late 80's was first synthesized domestic product class III nibentan, highly effective against various forms of MA. The drug effectively suppresses paroxysmal MA in 80-85% of cases and, most importantly, has the ability to medical cardioversion of chronic forms of MA with an efficiency of 75 to 80% . This score is 2-2 .5 times the efficiency of foreign drugs, which puts the drug in the first place of all synthesized and tested in the clinic medicines of this class. However nibentan not devoid of typical prioritiesin effects of drugs class II (although the probability was less than analogues), and therefore its application requires conditions of specialized cardiac chambers and blocks of intensive monitoring. The disadvantage nibentana its toxicity, it is not possible to create a tablet dosage form and to use it not only for relief, but also to prevent recurrence of AF.
Thus, at present, for General use there are only 2 drugs of this class: multiplicator amiodarone and sotalol. The first application, including MA, significantly limited uncertainity side effects, and the effectiveness of sotalol low. Dofetilide and ibutilide found limited use abroad and unavailable in Russia.
Object of the invention is the finding in a series of derivatives of piperidin-4-ethane compounds with high anti-arrhythmic and antifibrillatory activity and not showing or showing minimal prioritiesin and toxic properties.
The problem is solved by creating a connection - hydrochloride N-1-[(4-forfinal)-2-(1-ethyl-4-piperidyl)-ethyl]-4-nitrobenzamide represented by formula I. the prior art did not follow that the introduction of substituents contained in the inventive connection compared to, for example, with nibentana will lead to its properties, described below.
The scheme for synthesis of compound f is rmula I
The key compound in the synthesis of compound I is 1-(4-forfinal)-2-(4-pyridyl)-propionitrile (VI), which was obtained from 4-perforaciones (II) hydrochloride and 4-chloromethylpyridine (IV). Last translated into the base and are condensed with the sodium derivative of ethyl ether 1-(4-forfinal)-tsianuksusnogo acid (III), which, in turn, was obtained from 4-perforaciones (II), ethylate sodium and diethyl carbonate in toluene. Decarboxylation of ethyl ether 1-(4-forfinal)-1-cyan-2-(4-pyridyl)-propionic acid (V) was performed with an aqueous solution of potassium hydroxide. The output of "propionitrile" (VI) is 90%.
Hydrolysis "propionitrile" (VI) received "propionamide" (VII), alkylation of which leads to the formation of the Quaternary salt (VIII). The Quaternary salt (VIII) was obtained from (VII) and methyl ethyl in acetonitrile with the release of 90-95%.
By restoring the pyridine ring received alkyl substituted piperidinyl cycle. Investigated a number of catalysts and solvents, and the best results are obtained when the hydrogenation (VIII) over platinum oxide in methyl alcohol. The reaction ends for 14-16 hours. The yield is quantitative.
After hydrogenation of the hydrobromide of 1-(4-forfinal)-2-[4-(N-ethylpiperidine)]-propionamide (IX) baregreppro the Hoffman turned in "writeln" (X) in the presence of methylpiperid, which was obtained in the reaction of sodium methylate and bromine. The output stage is 85-90%. Then writeln" (X) is hydrolyzed to "Amin" (XI) in the presence of alkali in aqueous-alcoholic medium. 1-(4-forfinal)-1-amino-2-[4-(N-ethylpiperidine)]-ethane (XI) was purified by distillation in vacuum and are condensed with 4-nitrobenzylamine in acetonitrile, getting the final product (I).
Thus, the process of obtaining a sample of the compounds of formula I consists of 11 stages. All processes have a good reproducibility of the outputs and quality of intermediates. The example illustrates the final stage - the final product - the compounds of formula I.
Example. The hydrochloride of N-1-[(4-forfinal)-2-(1-ethyl-4-piperidyl)-ethyl]-4-nitrobenzamide (I)
In chetyrehosnuju round-bottom flask equipped with stirrer, thermometer, reflux with potassium chloride tube and a dropping funnel, download 9,72 g (of 0.038 mol) of 1-(4-forfinal-1-amino)-2-[4-(N-ethylpiperidine)]ethane and 15 ml of acetonitrile, stirred until complete dissolution at 20-25°C. To the resulting solution was added with stirring the solution was 7.45 g (0.04 mol) of p-nitrobenzaldehyde in 25 ml of acetonitrile with such speed that the temperature of the reaction mixture did not exceed 40°C. after the addition, the reaction the mass is heated to 50-52°C and kept at this temperature is 30-40 minutes The reaction mass under stirring spontaneously cooled to room temperature, then cold water to 5-10°C. and at this temperature, allowed to stand for 1 hour. Precipitated hydrochloride of N-1-[(4-forfinal)-2-(1-ethyl-4-piperidyl)-ethyl]-4-nitrobenzamide filtered off, washed with 25 ml of cold acetonitrile and dried at 40-45°C for 2 h, then at 80-85°C until constant weight, is recrystallized from ethanol with activated charcoal, obtain 14.3 g of the hydrochloride (yield after crystallization 86,3%) with TPL 218-227°C, CF C22H27N3O3FCl.
Found, %: C 60,74; N 6.35mm; N 9,45; Haltotal12,42.
Calculated, %: 60,61; N 6,24; N For 9.64; Haltotal12,49.
Compound I is a white with a greenish-yellow tint crystalline powder, odorless, soluble in water and alcohols.
IR spectrum (ν, cm-1): 1605 (C=C); 1655 (C=O); 3280 (NH).
An NMR spectrum1H (rest. DMSO-d6, STD. TMS): 10,08 (Sh.S., 1H, NH+; 9.28 are (d, 1H, J=8,3 Hz, NHCO); with 8.33 (d, 2H, J was 8.8 Hz) and to 8.14 (d, 2H, J=8,8 Hz): C6H4NO2(R); 7,49 (m, 2H) and 7,17 (m, 2H): C6H4F(R); further 5.15 (m, 1H, C(N)HCH2); to 3.41 (d, 2H, J=12,0 Hz, HeqCNCHeq); to 2.99 (m, 2H, NCH2CH3); 2,80 (m, 2H, HaxCNCHax); 1,50-2,00 (m, 7H, CH2CH(CH2)2).
The output of the compounds of formula I is 34.5%, counting on the 4-perforaciones.
Characterization of the biological active is STI the claimed compounds
1. The study antifibrillatory activity conducted on the model of the threshold electric fibrillation in cats of both sexes weighing 2-3,5 kg Fibrillation of the heart caused by a standard method by drawing on heart electrical stimulation. Evaluated the ability of the compounds to increase the threshold of fibrillation as compared with the initial reference value. For the original threshold atrial took the minimum value of the electric current in mA, which causes fibrillation. The results of the study are presented in table 1.
|ANTIFIBRILLATORY ACTIVITY AND DURATION of action of COMPOUND I WHEN administered INTRAVENOUSLY IN ANESTHETIZED CATS|
|Substance||Dose (µg/kg)||The threshold electric atrial left ventricular (mA)(M±m)||Duration (min)|
|Initial level||After 5 min after injection|
|Compound I (n=17)||1,0||1,9±0,3||3,3±0,4*||60,0|
|*p<0.05 compared with the initial level|
Thus, the dose of the claimed compounds I in which begins to change the threshold atrial 100 times less than sematilide, 500 times less than that of D-sotalol, 25 times less than nibentana, and comparable with dofetilide.
2. Antiarrhythmic activity of the compounds I with strofantinom arrhythmias was investigated in Guinea pigs weighing 260-400 g, anesthetized with urethane (1.6 g/kg). Disorders of heart rhythm caused intravenous strofantina G at a dose of 8 mg/kg for 30 seconds every 1.5 min until the death of animals. Found that in the studied dose of compound I prevented the occurrence of extrasystoles and increased dose strofantina causing ventricular fibrillation and death of animals (table 2). In similar conditions nibentan was ineffective against the occurrence of extrasystoles, and in relation to ventricular fibrillation and death of animals acted similar to compound I.
|ANTIARRHYTHMIC ACTIVITY of the COMPOUNDS I WITH STROFANTINOM ARRHYTHMIAS IN Guinea PIGS|
|Substance||Dose, mg/kg intravenous||Dose strofantina (%) needed to occur:|
|PVCs||ventricular fibrillation||of death|
|Compound I (n=3)||5||-||120||140|
Thus, compound I, like nibentana had a protective effect when strofantinom arrhythmias, although it was evident at a dose (5 mg/kg), significantly higher doses, effective on the model of threshold electrical ventricular fibrillation.
The study antiarrhythmic activity was also conducted on vagotomies model of atrial fibrillation in mongrel dogs of either Palmasol 10-20 kg, anesthetized with Nembutal and chloralose. Vazotonicheskih the atrial fibrillation caused by the introduction of bipolar electrodes in vagosympathetic trunks, cranial place of introduction of the electrodes was bandaged. After receipt of atrial fibrillation within 30 min (time irritation of the nerves) nerve stimulation was stopped and after 10 minutes the procedure was repeated again not less than 4 times. If every time the fibrillation was maintained for 30 minutes, started testing the compounds of formula I. the dose of 5 mg/kg compound I stopped fibrillation in 6 out of 8 experiments and in none did not prevent its re-occurrence. At the dose of 10 mg/kg compound I stopped fibrillation in 7 out of 8 experiments and one did not prevent it. At doses of 20 and 40 mg/kg compound I stopped fibrillation in all experiments and prevented its appearance in 3 and 4 cases, respectively.
3. Arrhythmogenic properties of compound I studied in experiments on rabbits anesthetized with urethane (1 g/kg, intraperitoneally) and chloralose (50 mg/kg) in the conditions of artificial respiration according to the method proposed by Carlsson et al. (1990). With this purpose, animals were first started intravenous infusion (external jugular vein) introduction methoxamine (provoking the emergence of arrhythmias) with a speed of 15 µg/kg/min and after 10 min after the start of injection of alpha-adrenomimetic simultaneously started infuse the traditional introduction (femoral vein) of compound I at doses of 0.2, 2, 20 and 200 mm for 30 min (in a volume of 0.1 ml/kg/min) until the occurrence of ventricular premature beats or tachycardia, which was detected by the electrocardiograph ACC-01.
Found that in the investigated range of doses of compound I does not show arrhythmogenic properties.
4. Refractory periods of atrial and ventricular fibrillation in dogs. Effective refractory periods (ETA) of the Atria and ventricles were determined in anesthetized dogs with an open chest and pericardium. The Atria and the ventricles were added bipolar electrodes and the heart of the imposed rhythm 15-20% above sinus. The intensity of the stimulus (S1) in 1.5-2 times above the threshold. After 18 stimuli (S1-S1) was applied stimulus S1-S2, with S2 was 3-4 times higher than the threshold. For ETA took the maximum interval S1-S2, which has not yet occurred spreading the answer. Significant increase in ETA in the Atria observed at the dose of 5 mg/kg at 16±5%, p<0.05 compared to control, and then the ETA grew almost linearly to 45±3%, p<0.001 at a concentration of 40 µg/kg In the ventricles significant increase in ETA observed at the dose of 40 mcg/kg (24±3%, p<0.05), dose of 80 mg/kg did not cause further growth ETA.
Compound I is significantly different from nibentana the effect on the refractoriness of the Atria and ventricles: nibentan at a dose of 125 mg/kg increases the refractoriness of atrial 15-20 MS, whereas the link is I in a dose of 20 mg/kg - 40-45 MS, i.e. at a dose of 6 times smaller, increases the refractory 2-3 times more, and the refractory ventricular significantly changed only at the dose of 40 mcg/kg Thus, compound I has a unique feature to influence mainly on atrial refractoriness, which dramatically reduces the likelihood of the development of polymorphic ventricular tachycardia, which is the main complications in the relief of atrial fibrillation, a dangerous fatal.
5. Ionic currents in cardiac fibers. The enzymatic isolated cardiomyocytes in the configuration of the hole cell attach used the standard method of fixing the potential for measurement of transmembrane ion currents. Found a dose-dependent blocking potassium current of the detained straightening on 10, 12 and 15% (p<0.05) at doses of the claimed compounds 0.1, 1.0 and 10 μm, respectively. Not detected changes facing short-term potassium current (Ito) and potassium currents anomalous rectification (IK1). Found a slight decrease in calcium current high conductivity, which maximally decreased when the dose of the claimed compound (10 μm.
Compound I does not show allergenic properties (tests of General anaphylaxis is an allergic shock reaction active cutaneous anaphylaxis, hypersensitivity reaction "slow" type psevdoallergicakie response to concanavalin a), not about lady ability to induce gene mutations, has no cytogenetic activity. LD50in mice when administered intravenously is 39.3 mg/kg
The present invention also extends to pharmaceutical preparations containing as active ingredient a compound of the formula I. the latter may be used either alone, or in combination with pharmaceutically acceptable carriers and components, selected based on the desired route of administration and conventional pharmaceutical practices. Possible dosage forms - injectable (intravenous), oral (tablets, capsules).
The compound of the formula I can be used for the treatment and prevention of various disorders of heart rhythm.
Currently, drug-based compound I undergoes allowed clinical trials.
1. The Cardiac Arrhythmias Suppression Trial (CAST) Investigators. // N.Engl. J.Med. 1989; 321:406-12.
2. Mortality in patients treated with flecainide and encainide for supraventricular arrhythmias. Am.J.Cardiol 1991; 67:976-980.
3. Quality of life and exercise performance in patients in sinus rhythm versus persistent atrial fibrillation. J.Am.Coll. Cardiol 2006; 48:721-730.
4. ACC/AHA/ ESC 2006 Guidelines for the management of patients with atrial fibrillation - full text. Europace 2006; 8:651-45.
5. Control of arrhytmias by selective lengthening of cardiac repolarization: theoretical considerations and clinical observations. Am. Heart J. 1993; 109: 421-30.
6. Arrhythmia control by prolonging repolarization: the concept and its potential therapeutic impact. Eur. Heart J. 1993; 14 (Suppl H): 14-23.
7. Efficacy of intrvenous ibutilide for rapid termination of atrial fibrillation and atrial flutter: a dose-response study. JACC, 1996 28; No. 1: 130-6.
8. Antiarrhythmic drug therapy: what is certain and what is to come. Eur. Heart J. Suppl. 2003, 5 H8-H18.
9. Creating original domestic anti-arrhythmic drugs class III. Vestn. Russian Academy of medical Sciences 2003; 12:61-65.
1. The hydrochloride of N-1-[(4-forfinal)-2-(1-ethyl-4-piperidyl)-ethyl]-4-nitrobenzamide formula
2. Drugs for prevention and treatment of cardiac arrhythmias comprising as active ingredient the compound according to claim 1.
FIELD: medicine, pharmaceutics.
SUBSTANCE: present invention refers to application in an effective amount and to new nicotine receptor agonists described by general formula (i) or (ii) for treating inflammatory diseases chosen from a group including asthma, chronic obstructive pulmonary disease (COPD), interstitial pulmonary tissue fibrosis (IPF), sarcoidosis, hypersensitivity pneumonitis (HP), chronic hypersensitivity pneumonitis and bronchiolitis obliterans organising pneumonia (BOOP). The compounds (i) and compounds (ii) relate to formulae (i) (ii) where in formula (i) R1 and R2 independently mean alkyl with 1-10 carbon atoms; Xa means CH or N; Ya means one or more substitutes chosen from hydrogen, halogen, cyano, hydroxyl, alkyl with 1-10 carbon atoms optionally substituted with one or more halogen atoms, and alkoxy with 1-10 carbon atoms; n means an integer 0 or 2; J means a counterion representing a compound for maintaining electric neutrality, e.g., halogen, sulphate, sulphonate; in formula (ii) R3 is chosen from or Xb means N or N+-R10; R4 means one or more substitutes chosen from hydrogen, halogen; each R10, R11 and R12 independently means alkyl with 1-10 carbon atoms; provided the presence of the counterion when Xb means N+-R10.
EFFECT: use of nicotine receptor agonists in the effective amount for treating inflammatory diseases.
26 cl, 40 dwg, 3 tbl, 38 ex
SUBSTANCE: present invention relates to a method for synthesis of 1-aminomethyl-2-phenylacetylenes of formula (1), where is characterised by that, phenylacetylene (Ph-C≡CH) is reacted with gem-diamines R2NCH2NR2, where R2N is as defined above, in the presence of a Sm(NO3)2*6H2O catalyst in molar ratio phenylacetylene: gem-diamine: Sm(NO3)2*6H2O=10:(8-12):(0.2-0.6) at 80°C and atmospheric pressure for 3-5 hours.
EFFECT: new method is designed for synthesis of 1-aminomethyl-2-phenylacetylenes, which can be used in fine organic synthesis, particularly for synthesis of scarce polycyclic compounds.
1 tbl, 1 ex
SUBSTANCE: invention relates to novel bioisosteres of actinonin of general formula (I) , as well as to pharmaceutically acceptable salts thereof and pharmaceutical compositions based on said compounds, with peptide deformylase (PDF) inhibitory activity, as well as to use of the compounds or pharmaceutical compositions based on said compounds to prepare medicinal agents. In general formula (I) R1 is a hydrogen atom, R2 is a hydrogen atom, (C1-C6)alkyl residue, hetero(C1-C6)alkylphenyl residue, where the heteroatom is sulphur, R3 is a hydrogen atom, R4 is (C1-C6)alkyl residue, (C3-C7)cycloalkyl residue, R6 is a hydrogen atom, n is 1, 2 or 3. Values of substitute R5 are given in the formula of invention.
EFFECT: new compounds have useful biological activity.
8 cl, 1 ex
SUBSTANCE: invention relates to method of obtaining substituted aminobenzhydrols, which can be used as semi-products in synthesis of medications of general formula , where: R1=R3=H, R2=NH2, R4=Cl (1); R1=R3=H, R2=NH2, R4=Br (2); R1=R3=H, R2=NH2, R4=OCH3 (3); R1=R4=H, R2=NH2, R3=Cl (4); R1=H, R2=NH2, R3=Cl, R4=Cl (5); R1=NH2, R2=Cl, R3=R4=H (6); R1=NH2, , R3=R4=H (7); R1=NH2, R2=Cl, R3=H, R4=Cl (8); R1=NH2, , R3=H, R4=Cl (9); R1=NH2, R3=Cl, R2=R4=H (10); R1=NH2, , R2=R4=H (11); R1=NH2, R2=H, R3=Cl, R4=Cl (12); R1=NH2, R2=H, , R4=Cl (13), whish lies in simultaneous reduction of nitro- and carbonyl groups of respective nitrobenzphenones of general formula , where: R1=R3=H, R2=NO2, R4=Cl; R1=R3=H, R2=NO2, R4=Br; R1=R3=H, R2=NO2, R4=OCH3; R1=R4=H, R2=NO2, R3=Cl; R1=H, R2=NO2, R3=Cl, R4=Cl; R,=NO2, R2=Cl, R3=R4=H; R1=NO2, , R3=R4=H; R1=NO2, R2=Cl, R3=H, R4=Cl; R1=NO2, , R3=H, R4=Cl; R1=NO2, R3=Cl, R2=R4=H; R1=NO2, , R2=R4=H; R1=NO2, R2=H, R3=Cl, R4=Cl; R1=NO2, R2=H, , R4=Cl, reducing system Zn-NaBH4 in alcohol with molar ratio of substratum : zinc: sodium tetrahydroborate equal 1 : 3.5 : 0.25.
EFFECT: reduction of synthesis cost, reduction of time and temperature for process carrying out, increase of target products output.
1 cl, 2 tbl, 13 ex
SUBSTANCE: present invention concerns the salts containing bis(trifluoromethyl)imide anions and saturated, partially or completely unsaturated heterocyclic cations, method of production and application thereof as ionic liquids.
EFFECT: production of new salts to be used as ionic liquids.
19 cl, 5 ex
SUBSTANCE: inventive subject matter is compouns and their pharmaceutically acceptable salts which can be applied in prevention and treatment of diseases caused by HCV infection. Structural formulae of the compounds are presented in the claim.
EFFECT: obtaining anti-HCV medicine including the claimed compound or its pharmaceutically acceptable salt as active component.
2 cl, 100 ex
FIELD: organic chemistry.
SUBSTANCE: invention relates to new method for production of compounds of general formula
R=-NH2, -NHCH2CH2OH, -NHCH2C6H5, -NHNHC6H3(NO2)2, -NHNH2, -NHNHC6H5, -NHCH2СН2NH2.
, , .
Claimed method includes interaction of 2-hydroxy-2-cyanoadamantane with ammonia or derivatives thereof such as piperidine, piperazine, 1,2-diaminoethane, etc, in ethanol medium, at 20-80°C for 8-72 h.
EFFECT: enhanced assortment of adamantine derivatives useful as synthetic intermediates for bioactive compounds, method of increased yield.
1 cl, 10 ex
FIELD: organic chemistry, medicine.
SUBSTANCE: invention relates to compounds of (R)-2-arylpropionamide of the formula (I): , wherein Ar means aryl of the formula (IIIb): F-Arb wherein Arb means phenyl mono- or poly-substituted with the following groups: chlorine, fluorine atom; F means hydrogen atom, linear or branched (C1-C5)-alkyl residue, benzoyl, 2,6-dichlorophenylamino-, 2,6-dichloro-3-methylphenylamino-group; R means hydrogen atom, (C1-C4)-alkyl; X means linear or branched (C1-C6)-alkylene optionally substituted with the group -CO2R4 wherein R4 means hydrogen atom or linear or branched (C1-C6)-alkyl group, phenyl or phenylmethylene group; R1, R2 and R3 mean independently linear or branched (C1-C6)-alkyl, (C3-C7)-cycloalkyl, (C3-C6)-alkenyl, aryl, aryl-(C1-C3)-alkyl, or R1 and R2 in common with nitrogen atom (N) to which they are attached form nitrogen-containing 6-membered heterocyclic ring of the formula (II) , and R3 has values indicated above independently wherein in the formula (II) Y means a simple bond, methylene group, oxygen atom, nitrogen atom or sulfur atom; p means a whole number 2; Z- means a pharmaceutically acceptable counterion of quaternary ammonium salts. Also, invention relates to using compound of the formula (I) in treatment of psoriasis, pemphigus and pemphigoid, rheumatic arthritis, intestine chronic inflammatory pathology including ulcerous colitis, acute respiratory distress-syndrome, idiopathic fibrosis, mucoviscidosis, pulmonary chronic obstructive disease and glomerulonephritis, and also for prophylaxis and treatment of injure caused by ischemia and reprefusion. Also, invention relates to a pharmaceutical composition possessing the inhibitory activity with respect to chemotaxis of polymorphonuclear leukocytes and monocytes induced by complement C5a fractions and comprising compound of the formula (I) in mixture with a suitable carrier. Also, invention relates to a method for synthesis of compounds of (R)-2-arylpropionamide of the formula (I) that involves interaction of amides of the formula (IV) given in the invention description with compounds of the formula R3Zwherein Z means a leaving group, such as chloride, bromide, iodide, methanesulfonate, p-toluenesulfonate, sulfate. Invention provides synthesis of (R)-2-arylpropionic acid omega-aminoalkylamide quaternary ammonium salts used for inhibition of chemotaxis activation induced by the C5a complement component.
EFFECT: valuable properties of compounds and pharmaceutical compositions.
17 cl, 1 tbl, 6 ex
FIELD: chemistry of metalloorganic compounds, agriculture.
SUBSTANCE: invention describes derivatives of mepiquate borate of the general formula (I): wherein DMP means N,N-dimethylpiperidinium (mepiquate); M means metal cation acceptable for agriculture and chosen from a series comprising sodium, potassium, magnesium, calcium, zinc, manganese or copper, hydrogen atom or NH4 +; O means oxygen atom; A means chelate of complex-forming fragment bound with one boron atom and representing (lower)-alkylglycols or sugars; n and m mean similar whole numbers in the range from 1 to 6; x means a whole or fraction number in the range from 0 to 10; y means a whole or fraction number in the range from 1 to 48; z means a whole or fraction number in the range from 0 to 48; v means a whole or fraction number in the range from 0 to 24, and w means a whole or fraction number in the range from 0 to 24. Also, invention describes methods for preparing compound of the formula (I) by interaction of N,N-dimethylpiperidinium hydroxide with boric acid and/or boron-containing oxides and optionally with metal hydroxides acceptable for agriculture indicated above or electrochemical method involving interaction of N,N-dimethylpiperidinium halide in the presence of water and boric acid and in the presence metal hydroxides acceptable for agriculture by bipolar electrodialysis. Invention describes electrochemical method for preparing N,N-dimethylpiperidinium hydroxide and a suspension concentrate possessing the plant growth-regulating effect prepared by mixing N,N-dimethylpiperidinium hydroxide, boron-containing compound chosen from boric acid and borate salt with a thickening agent and water, or by mixing compound of the formula (I) with Na2B8O13 x 4 H2O, a thickening agent and water. Prepared derivatives of mepiquate borate possess the improved indices of hygroscopicity and corrosion activity.
EFFECT: improved preparing methods, valuable properties of derivatives.
22 cl, 7 tbl, 16 ex
FIELD: organic chemistry, chemical technology, medicine, pharmacy.
SUBSTANCE: invention relates to a new biologically active compound. Invention describes quaternary ammonium derivative of lidocaine of the formula:
eliciting anti-arrhythmic activity. Also, invention describes a method for preparing quaternary ammonium derivative of lidocaine of the formula (1). Method involves interaction of N-(2,6-dimethylphenylaminocarbonylmethyl)-morpholine with allyl bromide in isopropyl alcohol medium at temperature 58-62°C followed by cooling the reaction mixture to room temperature and isolation of N-allyl-(2,6-dimethylphenylaminocarbonylmethyl)-morpholinium bromide. Invention provides preparing new compound eliciting useful biological properties.
EFFECT: improved preparing method.
2 cl, 4 tbl, 4 ex
SUBSTANCE: present invention relates to novel compounds of formula I: ,
to their synthesis method, a pharmaceutical composition based on said compounds and use of said compounds in making medicinal agents. Substitutes R1, R2, R4, R5, as well as values of A, B, D and n are given in the formula of invention.
EFFECT: obtaining novel compounds of formula I: ,
as well as their pharmaceutically acceptable salts which have inhibitory effect on cholesteryl ester transfer protein (CETP).
14 cl, 251 ex
SUBSTANCE: invention relates to the compounds of the formula and their pharmaceutically acceptable salts used as inhibiting agent in the relation of fermentative beta-secretase and it also relates to pharmaceutical compositions based on the formula. In general formula one of RN and RN' represents hydrogen, and another represents - C(=O)-(CRR')0-6R100, or where R4 is chosen from the group including H; NH2; -NR50CO2R51; -(C1-C4)-alkyl-NR50CO2R51; where n7 is equal to 0, 1, 2 or 3; R50 represents H or C1-C6alkyl; R51 is chosen from the group including phenyl-(C1-C4)-alkyl and (C1-C6)-alkyl; X is chosen from the group including -(C1-C6)-alkylidenyl optionally substituted with 1, 2 or 3 metal groups; Z is chosen from the group including bond, SO2, SO and S; Y stands for (C1-C10)-alkyl; R1 represents -(C1-C6)-alkylphenyl where phenyl ring is optionally substituted by 1, 2, 3 or 4 halogen atoms; R and R' independently represent hydrogen or (C1-C6)-alkyl; R2 represents hydrogen; R3 represents hydrogen; Rc represents - (CR245R250)0-4-aryl; where aryl is optionally substituted by 1, 2 or 3 R200; R200 is chosen from the group including (C1-C6)-alkyl optionally substituted with 1, 2 or 3 groups R205; halogen; C=N; R205 stands for halogen; R245 and R250 in each case stands for H; either R245 or R250 are taken together with carbon atom whereto attached to form carbocycle from 3, 4, 5, 6 or 7 carbon atoms; R100 represents 5-6-merous heteroaryl with 1-2 heteroatoms chosen from nitrogen and sulphur, -phenyl-W-heteroaryl where heteroaryl is 5-6-merous ring containing 1-2 heteroatoms, chosen from nitrogen and oxygen and where cyclic parts of each group are optionally substituted by 1, 2 or 3 groups independently chosen among C1-C6alkyl, -(CH2)0-4-CO2-NR105R'105, -(CH2)0-4-SO2-NR105R'105, -(CH2)0-4-N(R150)-CO-R105, -(CH2)0-4-N(R150)-SO2-R105; W represents -(CH2)0-4; R105 and R'105 independently represent (C1-C6)-alkyl optionally substituted with -NH2 or halogen; R150 represents hydrogen.
EFFECT: compounds can be applied to prevent and treat diseases mediated by excess activity of beta-secretase such as Alzheimer's disease.
11 cl, 12 tbl, 3 dwg, 1729 ex
FIELD: chemistry, pharmacology.
SUBSTANCE: invention relates to novel compounds -acidified arylcycloalkylamins of formula I in any of their stereoisomeric forms or in form of their mixture in any ratio, or their pharmaceutically acceptable salts, where in formula I : R1 represents aryl, not obligatory substituted with one or two similar or different substitutes, selected from group that includes C1-C6-alkyl and halogen; R2 represents aryl or heteroaryl, which represents residue of 5-6-member aromatic monocyclic heterocycle, containing 1-2 nitrogen atoms as heteroatom and/or 1 sulfur atom or oxygen atom, or residue of 9-10-member aromatic bicyclic heterocycle, containing 1-2 nitrogen atoms as heteroatom, each of which is unsubstituted or contains 1-3 similar or different substitutes, selected from group, consisting of halogens, NH2, unsubstituted C1-C10-alkyl, C1-C10 -alcoxy, C1-C10-alkylamino and di(C1-C10-alkyl)amino, and at least monosubstituted C1-C10-alkyl, etc., n represents 1, 2, 3 or 4. Invention relates to pharmaceutical composition, stimulating expression of endothelial NO synthase, based on said compounds, as well as application of compounds of formula I for production of medication for stimulating expression of endothelial NO-synthase and for treatment of such cardiovascular diseases as atherosclerosis, thrombosis, coronary artery disease, hypertension and impaired cardiac function.
EFFECT: invention ensures enhancing composition and treatment method efficiency.
9 cl, 2 tbl, 41 ex
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention describes acylated 6,7,8,9-tetrahydro-5H-benzocycloheptenylamines of the general formula (I): wherein R1 and R4 mean independently hydrogen atom (H), (C1-C10)-alkyl monosubstituted with fluorine atom (F); R2 and R3 mean independently H and (C1-C10)-alkyl; A means -CH, -CHOH; each among B, C and D means -CH2; R5 means possibly substituted phenyl or group Hetar. Also, invention describes method for synthesis of indicated compounds and a pharmaceutical preparation designated for stimulation of expression of endothelial NO-synthase. Nitrogen oxide (NO) released by endothelial tissue displays important significance in function of some main mechanisms of cardiovascular system. Nitrogen oxide exerts the vasodilating effect and inhibits platelets aggregation, adhesion of leukocytes to endothelial tissue and proliferation of smooth muscle cells in internal envelope of blood vessels.
EFFECT: valuable medicinal properties of compounds and pharmaceutical preparations.
16 cl, 1 tbl, 152 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention relates to pharmacology and organic chemistry and deals with novel quaternary ammonium derivative of Novocain of formula which possesses anti-arrhythmic activity, and method of its obtaining by interaction of Novocain base with bromide allyl in medium of isopropyl alcohol at temperature 57-63°C, holding at said temperature during 5-6 hours with following cooling of reaction mixture to room temperature and separation of N-allyl-N-(2-oxiethylcarboxy-4-aminophenyl)-diethylamine of bromide.
EFFECT: compound possesses useful biological properties.
2 cl, 2 tbl