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 [1]. 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 [2].

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 [3]. 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 [4].

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% [9]. 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.

Table 1
ANTIFIBRILLATORY ACTIVITY AND DURATION of action of COMPOUND I WHEN administered INTRAVENOUSLY IN ANESTHETIZED CATS
SubstanceDose (µg/kg)The threshold electric atrial left ventricular (mA)(M±m)Duration (min)
Initial levelAfter 5 min after injection
Compound I (n=17)1,01,9±0,3 3,3±0,4*60,0
5,02,2±0,215,9±1,6*>240,0
25,01,1±0,2<20,0>240,0
Sematilide (n=6)100,02,0±0,44,9±2,490,0
500,02,2±0,29,6±2,6*180,0
D-sotalol (n=5)500,01,1±0,42,2±0,760,0
1000,00,9±0,113,5±5,1*120,0
Dofetilide (n=18)1,02,6±0,26,8±2,3*60,0
5,02,7±0,314,2±1,9*>240,0
Nibentan (n=16)25,0 1,3±0,17,3±1,660,0
100,01,2±0,118,7±0,990,0
*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.

Table 2
ANTIARRHYTHMIC ACTIVITY of the COMPOUNDS I WITH STROFANTINOM ARRHYTHMIAS IN Guinea PIGS
SubstanceDose, mg/kg intravenousDose strofantina (%) needed to occur:
PVCsventricular fibrillationof death
Control-100100100
Compound I (n=3)5-120140
Nibentan (n=6)5100144134

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.

References

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.



 

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14 cl, 251 ex

FIELD: chemistry.

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

The invention relates to new Amida formula (1) (R1)(R2)-X-Y-Q-R3(1) where R1and R2taken together, constitute butylen or penttinen, each of which may be condensed with benzene, optionally substituted C1-C6alkoxy; R3represents phenyl, substituted with halogen, X represents CH, Y represents-NH - and Q is-C(O)-, provided that when R1and R2taken together, constitute butylen condensed with benzene, then indan ring formed when taking together R1, R2and S, substituted in position 2 by a group - Y-Q-R3and their salts

The invention relates to the field of organic chemistry

The invention relates to the field of organic chemistry, to the class of amides of aromatic amino acids, namely to a new biologically active amide N-(3'-harbutt-2'-yl) Anthranilic acid, which has anti-inflammatory activity, which may find application in medicine

The invention relates to amide derivatives of formula (I), where a is a monocyclic heteroaryl group, X is a bond or alkilinity group, R is hydrogen, halogen, alkyl, amino, arylalkyl group or halogen(aryl)alkyl group

The invention relates to new chemical compounds, specifically to the derivatives of amino acids, which exhibit antiarrhythmic activity and can be used in medical practice as anti-arrhythmic drugs

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The invention relates to a method for reducing the level of TNFin mammals and to compounds and compositions that are applied by this method

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

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