Nitrobenzamide, the pharmaceutical composition, its preparation and method of treatment and/or prevention of arrhythmias and ischemic heart rhythm disorders

 

(57) Abstract:

Describes the new nitrobenzamide represented by formula I, their salts or MES, where Ar denotes aryl, possibly substituted C1-6the alkyl, HE1-6alkoxyl; And means1-4n-alkylene, possibly substituted by 1 or 2 C1-6by alkyl; R is hydrogen, C1-6alkyl; one of R2, R3and R4means nitro and the other is hydrogen atom, X is-CO-NH-, Z means -(CH2)3-. Soedineniya formula I exhibit antiarrhythmic activity and have improved pharmacological characteristics compared with known anti-arrhythmic agents. Describes a pharmaceutical composition based on compounds of the formula I and its preparation and method of treatment and/or prevention of arrhythmias and ischemic heart rhythm disorders, including the introduction of an effective amount of the compounds of formula I. 4 C. and 8 C.p. f-crystals, 2 Il.

The invention relates to certain new compounds, pharmaceutical compositions containing such compounds, to a method for producing such compounds and method of using such compounds as therapeutic agents.

Antiarrhythmic agent classify I group block fast sodium channels drugs of group II are blockers beta-adrenergicheskih receptors, drugs III block potassium channels, IV drugs block calcium channels and drugs V group-specific depress sinus node.

Most ventricular arrhythmias and arterial connected with the circulation of excitation. The prolongation of refractoriness of the myocardium within or surrounded by such circulation of excitation is a potential mechanism for the treatment of cardiac arrhythmias.

As the drugs of group III antiarrhythmics block potassium channels in the heart, they prolong repolarization and increase refractoriness. Therefore, drugs class III represent the most specific group for the treatment of arrhythmias circulation of excitation.

However, because of their mechanism of action, i.e. dependent on the concentration with increasing duration of potential of cardiac contraction, higher doses of antiarrhythmic drugs III group may cause (induce) arrhythmia. Such arrhythmia called atrial represent the main side effect for all pure compounds of group III, currently under development.

In the European the antiarrhythmic drugs purely group III.

It has been discovered that certain new substituted 4-nitrobenzimidazole derivatives induce self-limiting increase in the potential duration of cardiac contraction associated with dual blockade of potassium and calcium channels in the heart. In accordance with this believe that they are applicable as antiarrhythmic drugs with improved pharmacological characteristics compared with antiarrhythmic means pure group III, in particular, believe that they are low proaritmicski potential and easily restore contractile function in ischemic myocardium. Believe that they are particularly useful in the treatment of atrial and ventricular cardiac arrhythmias.

Accordingly, the invention relates to new nitrobenzamide formula (I):

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or its salt, or its MES, where

Ar represents substituted or unsubstituted aryl, and optionally the substituents are selected from C1-6of alkyl, hydroxyl, C1-6alkoxyl;

A represents A C1-4n-alkylenes group, in which each carbon atom is optionally substituted by one or two C1-6alkyl groups;

R1represents hydrogen, C1-62, R3and R4represent hydrogen atoms;

X represents-CO-NH - component;

Z represents-CH2-CH2-CH2group.

Suitable substituents for Ar are 1 or preferably 2 CNS group, especially metaxylene group, and the substituents, preferably attached at the 3 - and 4-positions relative to the joining Ar to AC A.

Preferably Ar represents a 3,4-acid.

And may represent an unsubstituted C1-4n-alkylenes group.

Preferably A represents-CH2-CH2.

When R1is alkyl, it preferably is C2-6the alkyl, such as C2alkyl, C3alkyl, C4alkyl, C5alkyl or C6alkyl.

In one aspect, R1is alkylene or cycloalkyl.

Preferably R1is hydrogen.

Accordingly, any one of R2, R3and R4is a nitro-group, and the remaining members of R2, R3and R4represent hydrogen atoms.

Preferably R2is a 4-nitrogroup be unsubstituted C2-4n-alkalinous group.

Accordingly, Z may be CH2CH2CH2.

Particularly preferably the compound with the formula N-[3-[[2-(3,4-acid)ethyl] amino] propyl]-4-nitrobenzamide or its salt, such as cleaners containing hydrochloride salt, or MES.

As it is used here, unless otherwise indicated, the term "alkyl" includes alkyl groups with straight or branched chain, having from 1 to 12, preferably from 1 to 6 carbon atoms, and include such alkyl groups, which form part of other groups, such as CNS or arylalkyl group.

As it is used here, the term "alkylene includes alkylene group with a straight or branched chain, having from 2 to 12, preferably from 2 to 6 carbon atoms.

As it is used here, the term "cycloalkyl includes C3-8cycloalkyl groups, preferably of C5-6of carbon atoms.

As it is used here, unless otherwise indicated, the term "aryl" includes phenyl and naphthyl, preferably phenyl.

As it is used here, unless otherwise noted, "halogen" includes fluorine, chlorine or bromine.

As it is used here, the term "the heart aritmiami, premature contractions of the heart, heart block, atrial, fibrillation, tachycardia, paroxysmal tachycardia and premature contraction of the ventricles.

Compounds according to formula (I) may have chiral carbon atom (for example, when Z represents alkylenes group branched chain) and can therefore exist in more than one stereoisomeric form. This invention applies to any stereoisomeric forms, including enantiomers of the compounds according to formula (I) and mixtures thereof, including racemates. These stereoisomeric forms may be separated one from the other or decomposed conventional methods, or the given isomer may be obtained using conventional methods stereospecific or asymmetric synthesis.

Pharmaceutically acceptable salts of the compounds according to formula (I) include salts with the addition of acids with pharmaceutically acceptable mineral acids such as hydrochloric acid, Hydrobromic acid, boric acid, phosphoric acid, sulfuric acid, and pharmaceutically acceptable organic acids such as acetic, tartaric, maleic, citric, succinic, benzoic, ascorbic, methansulfonate, -Ketoglutarate drochloride.

Pharmaceutically acceptable salts include pharmaceutically acceptable N-oxides, and the invention applies to them.

Compounds according to formula (I) and their salts can also form a solvate, especially a pharmaceutically acceptable solvate such as a hydrate, and the invention extends to these solvate, and especially the pharmaceutically acceptable solvate.

Salt and/or solvate of the compounds according to formula (I), which are not pharmaceutically acceptable may be used as intermediates in obtaining pharmaceutically acceptable salts of the compounds according to formula (I) or of compounds according to formula (1), and as such constitute one aspect of the present invention.

The compound according to formula (I) or its salt, or its MES can be obtained by reacting the compounds of formula (II):

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where A, Ar, R1and Z are defined in formula (I) with the compound of the formula (III):

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where R2, R3and R4defined in formula (I), and L1represents a removable group; and thereafter, if necessary, carrying out one or more of the following optional steps:

(I) the conversion of compounds of formula (I) in the following connected to the SS="ptx2">

The compounds of formula (III) are known, commercially available compounds.

The reaction between the compounds of formulae (II) and (III) can be carried out in any suitable inert solvent such as dichloromethane, in the presence of a base, usually of an organic base, such as triethylamine, at a temperature that ensures the appropriate rate of formation of the required product, generally from low to room temperature, preferably at room.

Preferred removable group L1is a halogen atom such as chlorine atom.

The compounds of formula (II) are known compounds and can be obtained by the method described in Offenlegun-gsschrift 2345423.

The compounds of formula (II) can also be obtained by restoring the compounds of formula (IV):

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where A, Ar, and R1defined for the compounds of formula (I), a Z1represents a C1-3n-alkylenes group, in which each carbon atom is optionally substituted C1-6alkyl group.

The recovery of the compounds of the formula (IV) can be carried out using reducing substances, and under conditions, for example, by use of the metal is AK tetrahydrofuran, or diethyl ether, or mixtures thereof, at a temperature that ensures the appropriate rate of formation of the required product, generally at an elevated temperature and more conveniently at the boiling temperature of the solvent.

The compounds of formula (IV) can be obtained by reacting the compounds of formula (V):

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where A, Ar and R1defined for the compounds of formula (I) with the compound of the formula (VI):

H2N-CO-Z1-L2(VI)

The reaction between the compounds of formulae (V) and (VI) is carried out in an aprotic solvent such as acetonitrile, at a temperature that ensures the appropriate rate of formation of the required product, generally at an elevated temperature and it is more convenient at the boiling temperature of the solvent; preferably the reaction is carried out in the presence of a base, usually of an organic base, such as trialkylamine, such as triethylamine, or complex, such as potassium fluoride on celite (Takashi Ando, junkō Yamawaki, Chemistry Letters, 1979, p. 45).

Preferred removable group L2is a halogen atom such as chlorine atom.

Compounds of the formula (V) are known, commercially available compounds.

Compounds of the formula (VI) receipt of known commercially available compounds.

In an additional aspect this invention is a method of obtaining the compounds of formula (I), a method which involves demethylation of compounds of formula (VII):

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where A, Ar, R2, R3, R4, X and Z have the same definitions as in formula (I), and then, if necessary, the transformation of any-NH-group, formed thus, in group NR5where R5represents a C2-6alkyl, alkenylphenol or cycloalkyl group.

Demethylation of compounds of the formula (VII) can be performed by using the conventional way demethylation, for example by using the methods described in J. Org. Chem., 1975, 40, 1850, ibid, 1984, 49, 2081, or those methods described in Synthesis 1991, 318.

The transformation of any-NH-group NR5where R5represents a C2-6alkyl, alkenylphenol or cycloalkyl group, can be carried out using conventional methods of alkylation, alkenylamine or cycloalkylcarbonyl by using proper alkylhalogenide, alkenylsilanes or cycloalkylcarbonyl, more suitable iodide, in the presence of a base, such as potassium bicarbonate, in an aprotic solvent such as tetrahydrofuran.

The compound of formula (I) or its salt, or its MES can also be obtained by reacting the compounds of formula (VIII):

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where R2TO3, R4, X and Z have the same definitions as in the formula (1), and LS is a removable group, such as halogen, with a compound of formula (IX):

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where A, Ar, R1have the same definitions as in formula (I); and then, if necessary, by carrying out one or more of the following optional steps:

(I) the conversion of compounds of formula (I) in the following compound of formula (I);

(II) obtain the salts of the compounds of formula (I) and/or its pharmaceutically acceptable MES.

The reaction between the compounds of formulas (VIII) and (IX) can be carried out in any inert solvent, such as dichloromethane, in the presence of a base, usually of an organic base, such as triethylamine, at a temperature that ensures the appropriate rate of formation of the required product, generally at an elevated temperature, such as the boiling point of the solvent.

A more appropriate value for L3is the chlorine atom.

The compound of formula (VIII) can be obtained by reacting compounds of the above form is, THE L3has the same definition as in the formula (VII).

The reaction between the compounds of formulae (III) and (X) may be carried out under appropriate conditions of acylation, for example in an inert solvent, such as dichloromethane, in the presence of a base, usually of an organic base, such as triethylamine, at a temperature that ensures the appropriate rate of formation of the required product, generally from low to room temperature, preferably at room temperature. The compounds of formula (X) are known, commercially available compounds. The corresponding conversion of one compound of formula (I) in the following compound of formula (I) includes an intermediate transformation variable R1in the compounds of formula (I), for example the transformation of compounds in which R1is H, the compounds of formula (I), where R1represents alkyl, more acceptable C2-6alkyl, alkenyl or cycloalkyl, or the above-mentioned transformation of compounds, where R1is stands, in compounds, where R1is hydrogen, C2-6the alkyl, alkenyl or cycloalkyl.

It will be clear that when any of the above reactions and transformations of any reactive Ganja and removal of such protecting groups are generally accepted methods, suitable for molecules that you want to protect.

As mentioned above, it is shown that the compounds of this invention possess useful therapeutic properties. This invention, accordingly, is a compound according to formula (I) or its pharmaceutically acceptable salt and/or its pharmaceutically acceptable MES as an active therapeutic agent.

More specifically, this invention is a compound of formula (I) or its pharmaceutically acceptable salt and/or its pharmaceutically acceptable MES used for the treatment and/or prevention of arrhythmia, especially cardiac arrhythmias, such as ventricular fibrillation, and ischemic arrhythmias.

The compounds of formula (I) or its pharmaceutically acceptable salt and/or its pharmaceutically acceptable MES can be introduced in pure form or, preferably, in the form of a pharmaceutical composition that also includes a pharmaceutically acceptable carrier.

Accordingly, this invention is also a pharmaceutical composition comprising a compound of General formula (I) or its pharmaceutically acceptable salt, or pharmaceutically acceptable MES what I Sol, and/or its pharmaceutically acceptable MES are usually put in single dosage form.

Amount effective for treating the diseases described herein above depends on such factors as the effectiveness of the compounds of formula (I), the specific nature of the selected pharmaceutically acceptable salt or pharmaceutically acceptable MES, nature and severity of diseases that should be treated, and weight of the mammal. However, a single dose will normally contain 0.1 to 500 mg, for example 2-50 mg of the compounds of this invention. Single dose usually given one or more times a day, for example 2, 3, 4, 5 or 6 times a day, more usually 2 to 4 times a day, so the total daily dose is normally in the range, for the weight of an adult of 70 kg, from 0.1 to 2500 mg, more usually from 1 to 1000 mg, for example 1 to 200 mg, i.e. in the range of about 0.02 to 3 mg/kg/day, more typically 0.1 - 3 mg/kg/day, for example 0.15 to 2 mg/kg/day.

In the above doses for the compounds according to the invention no toxic effects were not found.

During such treatment the compound may be administered by any appropriate route, for example orally, parenterally or topically. In this case, the connection obychnom media diluent and/or excipient, although the exact form of the composition will, of course, depend on the method of administration.

The composition obtained by mixing, and they are respectively adapted for oral, parenteral or topical application and, as such, can be in the form of tablets, capsules, oral liquid preparations, powders, granules, tablets, diluted powders, solutions or suspensions for injections and infusions, suppositories, and transdermal preparations. Preferred oral input composition, as they are more convenient for everyday use.

Tablets and capsules for oral administration are usually presented in a single dose and contain conventional excipients such as binding agents, fillers, solvents, tabletiruemye tools, sliding substances, disintegrant tinted substances, substances that improve the taste, and moisturizing agents. Tablets may be coated according to well-known in this region methods.

Suitable for use fillers include cellulose, mannitol, lactose and other similar substances. Suitable disintegrant include starch, polyvinyl, for example, magnesium stearate. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.

Solid oral compositions may be obtained by conventional methods of blending, filling, tabletting and the like. Re-blending operation can be used to distribute the active substance in these compositions with the use of large quantities of fillers. Such operations, of course, well known in this field of technology.

Oral liquid preparations may, for example, be in the form of aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for dissolving water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspendresume substances, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, gel, aluminum stearate or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate or acacia gum. Non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated Colorker methyl - or propyl-p-hydroxybenzoate or sorbic acid, and, if desired, conventional improving the taste and smell and tinted substance.

For parenteral administration receive a disposable liquid dosage forms, containing a compound of this invention and a sterile carrier. This compound, depending on the carrier and concentration, can be either suspended or dissolved. Parenteral solutions are normally prepared by dissolving the active compound in the medium and sterilized by filtration before filling suitable vessel or ampoule and sealing.

Adjuvants such as local anesthetics, preservatives and buffering agents, it is also advisable to dissolve in the medium. To increase the stability of the composition can be frozen after filling of the vessel, and the water can be removed under vacuum.

Parenteral suspensions receive essentially the same way, except that the active connection suspendered in the media instead of dissolution and sterilized by exposure to ethylene oxide before suspendirovanie in sterile media. It is advisable to include in the composition a surfactant or wetting agent to facilitate uniform distribution of the active soy is for systemic delivery of compounds and can be produced in the usual way, for example, as described in standard handbooks, such as Dermatological dosage forms" - B. W. Barry (Drugs and the Pharmaceutical Sciences - Dekker) or Harrys Cosmetiology (Leonard Hill Books).

In addition, such compositions can contain additional active substances, such as antihypertensive agents and diuretics.

In accordance with usual practice, the compositions will usually be accompanied by written or printed instructions for use for the treatment in medicine.

As it is used here, the term "pharmaceutically acceptable" comprises compounds, compositions and ingredients for use in medicine for the treatment of human and veterinary medicine: for example, the term "pharmaceutically acceptable salt" includes salts that are acceptable for veterinary use.

This invention also provides a method of treatment and/or prevention of arrhythmia, especially cardiac arrhythmias, such as ventricular fibrillation, and ischemic arrhythmias in humans and other mammals, which includes the introduction of effective, non-toxic amount of compound of General formula (I) or its pharmaceutically acceptable salt and/or its pharmaceutically acceptable MES cheloveka pharmaceutical composition, which defined here earlier, and it represents a special aspect of the present invention.

In the treatment and/or prevention of arrhythmia and/or ischemic arrhythmias compound of General formula (I) or its pharmaceutically acceptable salt and/or its pharmaceutically acceptable MES can be taken in doses, such as described above.

Similar dosing regimens suitable for the treatment and/or prophylaxis and animals-mammals.

In the following aspect, the invention provides a method of using compounds according to formula (I) or its pharmaceutically acceptable salt and/or its pharmaceutically acceptable MES for production of medicaments for the treatment of arrhythmia, especially cardiac arrhythmias, such as ventricular fibrillation, and ischemic arrhythmias.

No Toxicological effects have been identified, when the compound of formula (I) or its pharmaceutically acceptable salt and/or its pharmaceutically acceptable MES used in the above dosing intervals.

The following description and examples illustrate the invention but does not limit.

Description 1

3-[[2-(3,4-Acid)ethyl]metamina and 7.7 g (75 mmol) of triethylamine in 100 ml of acetonitrile was stirred at the boil for 18 hours. The reaction mixture was concentrated in vacuo and the residue was purified by chromatography on silica gel using methylene chloride/methanol: 92/8 obtaining 5,12 g (64, 1%) of the desired compound as an orange oil.

1H NMR (CDCl3) = 2.40 a (s, 3H, NCH3); the 2.46 (t, 2H, J=5,9 Hz, CH2); 2,74 - 2,79 (Wed, 6H, 3CH2); of 3.85 and a 3.87 (2s, 6H, 2CH3O); 6,70 - 6,78 (Wed, 3H, 3Ar); 7,71 (Shir. band, 2H, exchange rate. D2O, NH2) memorial plaques

Description 2

N-[2-(3,4-Acid)ethyl]-M-methyl-1,3-propandiamine

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1.5 g (5.6 mmole) 3-[[2-(3,4-Acid)ethyl]methylamino] propanamide (D1) in anhydrous tetrahydrofuran was added dropwise to a suspension of 0.64 g (1.7 mmole) of sociallyengaged in 20 ml of anhydrous diethyl ether under stirring. The mixture was heated at boiling in a flask under reflux for 2 hours, then cooled in a bath of ice water before added carefully dropwise 0,65 ml of water,1 0,65 ml of 15% aqueous NaOH solution, then 1,95 ml of water. The mixture was dried over MgSO4concentrated in vacuo and the residue was purified twice by chromatography on basic alumina using methylene chloride/methanol: 95/5, then methylene chloride/methanol/30% aqueous ammonium: 90/10/0,1 obtaining 0,86 g (60.8 per cent) telemag>; of 2.30 (s, 3H, NCH3); 2,47 (t, 2H, J1- 7,4 Hz, CH2), 2,53 - 2,79 (Wed, 6H, 3CH2); of 3.85 and a 3.87 (2s, 6H, 2CH3O); of 6.71 - 6,82 (Ls, 3R, 3Ar) M. D.

Description 3

N-(3-Chloropropyl)-4-nitrobenzamide

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The solution to 6.43 g (49 mmol) of 3-chloropropylamine and 13.6 ml (98 mmol) of triethylamine in 220 ml of methylene chloride was cooled in an ice bath and added 9 g (48.5 mmol) of 4-nitrobenzylamine. After stirring for 1 hour at room temperature the organic phase is twice washed with water, dried over MgSO4and concentrated in vacuum to obtain for 10.68 g (91%) of beige crystals.1H NMR consistent with the desired structure.

Example 1

N-[3-[[2-(3,4-Acid)ethyl] methylamino] propyl]-4 - nitrobenzamide chloride

< / BR>
800 mg (3,17 mmole) of N-[2-(3,4-acid)ethyl]-N-methyl-1,3-propandiamine (D2), 630 mg (3.33 mmole) of 4 - nitrobenzylamine and 0.35 g (3,49 mmole) of triethylamine in 30 ml of methylene chloride was stirred for 2 hours at room temperature. The mixture was washed with water, dried over MgSO4and concentrated in vacuum. The residue was twice purified by chromatography on silica gel using methylene chloride/methanol: 97/3, then 94/6 receiving 700 mg (55%) of the desired compound in the form of a Foundation. It is connected to the re, getting 594 mg (43%) of the desired compound as a yellow solid: so pl. = 80 - 90oC (see Fig. 1).

1H NMR (DMSO-d6) = 2,00 (Wed, 2H, CH2); and 2.79 (s, 3H, NCH3); 2,90 (Wed, 2H, CH2): 2,95 (Wed, 2H, CH2); 3,20 (Wed, 2H, CH2); 3,35 (Wed, 2H, CH2); and 3.72 and 3.74 (2s, 6H, 2CH3O); 6,80 - of 6.96 (cf., 3H, Ar); to 8.12 (d, 2H, J 7.9 Hz, Ar); with 8.33 (d, 2H, J 7.9 Hz, Ar); 9,05 (user. band, 1H, exchange rate. D2O, NH); 10,45 (Shir. band, 1H, exchange rate. D2O, NH) M. D.

Example 2

N-[3-[[2-(3,4-Acid)ethyl]amino]propyl]-4-nitrobenzamide chloride

< / BR>
The solution to 10.62 g (44 mmole) of M-(3-chloropropyl)-4 - nitrobenzamide (D3) and 8.1 g (45 mmol) of homoveratrylamine and 6.26 ml of triethylamine in 200 ml of methylene chloride was heated at the boiling temperature in the flask under reflux for 48 hours. The solvent was then concentrated in vacuo and the residue was dissolved in water. The aqueous phase is first washed with methylene chloride, and then conveyed to the alkaline aqueous solution of NaOH and finally was twice extracted with methylene chloride. This second organic phase is dried over MgSO4and concentrated in vacuum to obtain 12 g of the crude residue. This residue was purified by chromatography on silica gel using CH2Cl2/MeOH/NH4OH: 85/10/5 with receipt is in methanol and acidified with a solution of anhydrous hydrogen chloride in diethyl ether, getting after drying 4.4 g of the compound of the title in the form of light beige crystals. So pl. 141-2oC (see Fig. 2).

1H NMR (DMSO-d6) = 1,93 (cp, 2H, CH2); 2,89 - 3,16 (cf., 6H, 3xCH2); 3,40 (Wed, 2H, CH2); 3,72 and 3.75 (2s, 6H, 2xOCH3); 6,74 - 6,91 (cf., 3H, Ar); 8,12 (D. , 2H, J 8.6 Hz, Ar); 8,32 (d, 2H, J = 8.6 Hz, Ar); 9,12 (Shir. band, 2H, exchange rate. D2O, NH2+); to 9.15 (t, 1H, exchange rate. D2O, NH) M. D.

Pharmacological data

Methodology

Guinea pigs (300-350 g) were doing anesthesia by intravenous injection of pentobarbital sodium (60 mg/kg). After thoracotomy, the heart was rapidly dissected and placed in oxygenated solution of Tyrode. Papillary muscles from the right ventricle was removed. The drugs are then recorded on elastically the basis of a 5 ml organ bath and poured oxygendemanding solution of Tyrode supported temperature 371oC.

A modified solution of Tyrode (pH 7,35) contained the following (mm): NaCI 125, KCl 4,0, MgCI20,5, CaCl21,8, NaHCO324, NaH2PO40.9 and glucose of 5.5. The solution was balanced by a gas mixture of 95% O2- 5% CO2. After the stabilization period (at least 1 hour) was measured transmembrane action potentials using conventional microelectrodes (10 MW), soedinennyh electrodes, placed at the end of the muscle. The pulse duration was 1 MS, and the amplitude was twice the threshold. The duration of the basic cycle was 1000 MS (stimulator PULSAR 6i). The signals observed on a storage oscilloscope (GOULD 1602) and simultaneously recorded on a digital recorder (BIOLOGIC DTR 1200) for further analysis.

Made measurements of the amplitude of the action potential (APD) and the duration of the action potential at 30 and 90% repolarization (PDSO and PPD respectively). Registration was made 30 minutes after balancing each concentration. For the analysis used only those readings in which the same boundaries remained during the whole experiment.

1. Nitrobenzamide formula I

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or its salt or solvate,

where Ar represents a substituted or unsubstituted aryl, and optionally the substituents are selected from C1-6of alkyl, hydroxyl, C1-6alkoxy;

A represents A C1-4n-alkylenes group, in which each carbon atom is optionally substituted by 1 or 2 C1-6alkyl groups;

R1is hydrogen, C1-6alkyl,

one or two of the groups R2, R3and Rs hydrogen;

X represents-CO-NH-,

Z represents-CH2-CH2-CH2group.

2. Connection on p. 1, where Ar represents a substituted or unsubstituted phenyl group.

3. Connection under item 1 or 2, where Ar represents a phenyl group substituted by 1 or 2 C1-6CNS groups.

4. The compound according to any one of paragraphs.1 to 3, where R1represents hydrogen.

5. The compound according to any one of paragraphs.1 to 4, where one of R2, R3and R4is a nitro-group, and other members of the group R2, R3and R4represent hydrogen atoms.

6. Connection on p. 5, where R2represents 4-nitro-group, and R3and R4each represents hydrogen.

7. Connection on p. 1, which is N-[3-[[2-(3,4-acid)ethyl)] amino]propyl]-4-nitrobenzamide, or its salt, or its MES.

8. Pharmaceutical composition having anti-arrhythmic activity, including an active ingredient and a pharmaceutically acceptable carrier, wherein the active ingredient is used as a compound of formula I under item 1, or its pharmaceutically acceptable salt and/or its farmatsevticheskii acceptable salt and/or its pharmaceutically acceptable MES for use as an active therapeutic substance.

10. The compound of formula I under item 1 or its pharmaceutically acceptable salt and/or its pharmaceutically acceptable MES with antiarrhythmic activity.

11. A method of obtaining a pharmaceutical composition having anti-arrhythmic activity by shifting the active ingredient and pharmaceutically acceptable carrier, wherein the active ingredient is used as a compound of formula I or its pharmaceutically acceptable salt and/or its pharmaceutically acceptable MES.

12. The method of treatment and/or prevention of arrhythmias and ischemic arrhythmias in humans and other mammals, including the introduction of effective non-toxic amount of a substance in need this person or mammal, characterized in that the active substance is used as a compound of General formula I or its pharmaceutically acceptable salt and/or its pharmaceutically acceptable MES.

 

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where R1denotes A, CF3CH2F, CHF2C2F5, CN, NO2, Gal, CCH, or-X-R4;

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R4denotes H, a, cycloalkyl with 5-7 C atoms, cycloalkenyl with 6-8 C atoms, CF3CH2F, CHF2CH2CF3Ph or-CH2-Ph;

R5denotes H or A, or, however,

R4and R5together also denote alkylene with 4-5 C atoms, and one CH2the group may also be replaced by O, S, NH, N-A or N-CH2-Ph;

R6denotes A or Ph;

Het denotes a dual core, saturated, unsaturated or aromatic heterocycle with 1 to 4 N, O and/or S atoms, linked via N or C, which is unsubstituted or may be substituted by one, two or three times with Gal, CF3, A, -X-R4, CN, NO2and/or carbonyl oxygen;

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"n" is 1 or 2; and

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The invention relates to sulfur-containing derivative of an aryl having antibacterial and antiviral activity, in particular Aristotelianism the following formula (I), their pharmaceutically acceptable salts and solvate, a pharmaceutical composition having antibacterial and antiviral activity, and method of treating bacterial or viral infections
The invention relates to medicine, gastroenterology, and for the treatment of patients with pyloroplasty ulcers, combined with duodenogastric reflux

The invention relates to medicine, can be used in the production of pharmaceuticals and for the creation of tools for healing of purulent-necrotic wounds of different etiology
The invention relates to medicine and relates to antimicrobial compositions containing chloramphenicol, castor oil, emulsifier, preservative, sodium carboxymethyl cellulose and water
The invention relates to medicine, surgery may be used in the surgical treatment of hydatid liver

The invention relates to new Amida aminocarbonyl acids of the General formula:

< / BR>
where R1, R2, R3, R4, R5and "n" and "m" have the following meanings:

R1, R2denote hydrogen, linear or branched (C1-C8)-alkyl;

(C3-C8-cycloalkyl as cyclohexyl; phenyl, which can be single or twofold substituted linear (C1-C4)-alkyl, (C1-C2-alkoxyl, halogen, cyano group, nitro group, trifluoromethyl or acylamino group; phenylalkyl, where the alkyl chain may contain 1-3 C-atoms and a phenyl ring, which may be single or twofold substituted stands, methoxy group, halogen, nitro group, cyano group or acylamino-group;

< / BR>
denotes a morpholine or piperidine which may be substituted by one or twice (C1-C2)-alkyl group or a group

< / BR>
where R6may denote H, NHCО2CH2CH3;

R3does

< / BR>
represents piperidine or morpholine

n = 1-5;

m = 2-4;

their physiologically acceptable salts joining acids, method of production thereof, and to pharmaceutical compositions and their use as pharmaceuticals, in particular for the treatment of cardiac arrhythmias
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