Amides aminocarbonyl acids, method for their production and pharmaceutical composition

 

(57) Abstract:

Amides aminocarbonyl acids of the formula I, where R1, R2- H, C1-8-alkyl, C3-8-cycloalkyl; phenyl or phenylalkyl, possibly substituted by alkyl, alkoxyl, halogen, cyano, nitro, CF3or allmineral; or R1-N-R2denotes a morpholine, piperidine or group (a) or (b), R3-CO-R7or O2S-C6H4-R8(the values of other radicals see item 1 of the claims), and their physiologically acceptable salts and pharmaceutical compositions based on them are a new antiarrhythmic agent. 3 S. and 2 C.p. f-crystals, 3 PL.

R1(R2)N-CO-(CH2)n-N(R3)-(CH2)m-N(R4R5(I)

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, which may contain 1-3 C-atoms and the phenyl ring, which can 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, NHC2CH2CH3;

R3does

< / BR>
where R7means (C3-C7-cycloalkyl such as cyclohexyl; phenyl, which may be single or twofold substituted linear (C1-C4)-alkyl, (C1-C2-alkoxyl, halogen, cyano group, nitro group, trifluoromethyl, sulfonamide group, methanesulfonamido group or acylamino-group;

phenylalkyl, where the alkyl chain may contain 1-3 C-atoms and the phenyl ring may be single or twofold substituted stands, methoxy group, halogen, nitro group, cyano group or arylaminopoly; and

R8may denote hydrogen or alluminare;

R4, R5denotes a linear or branched (C1-C6)-alkyl, (C3-C6-cycloalkyl as cyclohexyl; phenyl; phenylalkyl, where the alkyl group can contain 1-3 C-atoms or

prisoedinenia acids, the method of production thereof, and to pharmaceutical compositions and their use as pharmaceuticals, in particular for the treatment of cardiac arrhythmias.

Medicines for the treatment of cardiac arrhythmias based on their mechanism of action by Vaughan Williams (J. Glin. Pharmacol. 1984, 24, 129-147) divided into 4 classes:

class I: antagonists of sodium, which are further divided into classes IA, IBand IC;

class II: blockers of receptors;

class III: blockers of potassium channels (inhibitors of repolarization);

class IV: calcium antagonists.

Used still antiarrhythmic agent, which in the vast majority belong to the class I have only minor therapeutic latitude. In particular antiarrhythmic agent of class ICas research has shown, CAST (N. Engl. J. Med. 1991, 324, 781-788), not able to reduce mortality over time in patients with myocardial infarction. Mortality in the group in which injected a drug (Verum group) is even higher than in the group that administered a placebo. The reason that indicate pruritogens properties of antiarrhythmic drugs class I, which is reduced to slow provea class III, which is called as inhibitors of repolarization, in contrast, is particularly effective when you arrhythmias; as they lengthen the protective area is additionally called a disorderly irritation in the late phase of repolarization (the so-called effective refractory phase), without affecting the speed of the proceedings.

Input antiarrhythmic agent with properties of class III Amiodarone and Sotalol therefore better suitable for the treatment of cardiac arrhythmias than antiarrhythmic agent of class I.

Based partly serious side effects, particularly in the case of Amiodarone, these medicines are also only partially applicable.

Therapy of life-threatening arrhythmias, which only in the United States each year get sick more than 1 million people, and the prevention of sudden death from cardiac arrest, then, is an unsolved problem, so there is a great need for anti-arrhythmic means with improved properties.

Therefore, the basis of the invention is to obtain new compounds with improved antiarrhythmic efficacy and greater therapeutic latitude of action.

For The(I), where R1-R5"n" and "m" have the above significance, and their physiologically acceptable salts accession acids.

Compounds of General formula (I) in special and patent literature is still not described.

As examples of compounds of formula (I) of the present invention should be called:

/(4-acetylamino-benzazolyl)-(2-diethylamino-ethyl)- amino/-N,N-dicyclo-hexyl-ndimethylacetamide;

N-(DICYCLOHEXYL-carbamoylmethyl)-N-(2-diethylamino-ethyl)-3-methoxy-4-nitro-benzamide;

4-cyano-N-(DICYCLOHEXYL-carbamoylmethyl)-N-(2-diethylamino-ethyl)-benzamide,

4-chloro-N-(DICYCLOHEXYL-carbamoylmethyl)-N-(2-diethylamino-ethyl)-3-nitro-benzamide;

N-(2-dicyclohexylamine-carbamoylmethyl)-N-(3-diethylamino-propyl)-4-trifluoromethyl-benzamide;

4-acetylamino-N-(3-dibutylamino-propyl)-N-(DICYCLOHEXYL-carbarnoyl-methyl)-benzamide;

N-/5-(DICYCLOHEXYL-carbarnoyl)-pencil/-N-(2 - diethylamino-ethyl)-4-nitro-benzamide;

4-amino-N-(DICYCLOHEXYL-carbamoylmethyl)-N-(3-diethylamino - propyl)-benzamide;

N-(DICYCLOHEXYL-carbamoylmethyl)-N-(3-diethylamino-propyl)-4-nitro-benzamide;

N-(DICYCLOHEXYL-carbamoylmethyl)-N-(3-diethylamino-propyl)-2-nitro-benzamide;

4 carbamaxepine-N-(DICYCLOHEXYL-carbamoylmethyl;

N-(DICYCLOHEXYL-carbamoylmethyl)-N-(3-diethylamino-propyl)-3-nitro-benzamide;

N-(DICYCLOHEXYL-carbamoylmethyl)-N-(3-dimethylamino-propyl)-4-nitro-benzamide;

4-acetylamino-N-(DICYCLOHEXYL-carbamoylmethyl)-N-(3-diethylamino-propyl)-benzamide;

N-(DICYCLOHEXYL-carbamoylmethyl)-N-(2-diethylamino-ethyl)-4-nitro-benzamide;

4-acetylamino-N-(DICYCLOHEXYL-carbamoylmethyl)-N-(2 - diethylamino-ethyl)-benzamide;

N-(DICYCLOHEXYL-carbamoylmethyl)-4-nitro-N-(2-piperidine-1-yl-ethyl)-benzamide;

4-acetylamino-N-(benzyl-methyl-carbamoylmethyl)-N-(3-diethylamino-propyl)-benzamide;

N-(DICYCLOHEXYL-carbamoylmethyl)-N-(3-diethylamino-propyl)-4-methanesulfonamido-benzamide;

N-(DICYCLOHEXYL-carbamoylmethyl)-N-(3-diethylamino-propyl)-4-methanesulfonamido-benzamid-yodmetilat;

N-(DICYCLOHEXYL-carbamoylmethyl)-N-(3-morpholine-4-yl-propyl)-4-nitro-benzamide-yodmetilat;

N-(3-diethylamino-propyl)-N/2-(10,11-dihydro-dibenzo/b, f//azepin-5-yl)-2-oxo-ethyl/-4-nitro-benzamide;

N-(2-diethylamino-ethyl)-4-nitro-N-(2-oxo-2-piperidine-1-yl-ethyl)-benzamide;

N-(benzyl-methyl-carbamoylmethyl)-N-(2-diethylamino-ethyl)-4-nitro-benzamide;

N-(DICYCLOHEXYL-carbamoylmethyl)-N-(2-diethylamino-ethyl)-4-methanesulfonyl-amino-benzamide;

N-(3-dieti-yl-2-oxo-ethyl)-4-nitro-benzamide;

N-/2-(3-carbethoxy-amino-10,11-dihydro-dibenzo/b, f/azepine-5-yl)-2-oxo-ethyl/-N-(2-diethylamino-ethyl)-4-nitro-benzamide;

8-chloro-5 - {N-/3-(diethylamino)propan-1-yl/-N-(p-methylsulfonylbenzoyl)/-aminoacetyl}-5,10-dihydro-11H-dibenzo/b,e/ /1,4/diazepin-11-he;

8-chloro-5-{ /6-/N-(3-diethylamino)propan-1-yl/-N - benzoyl/-amino-1-oxo-hexyl}-5,10-dihydro-11N-dibenzo/b,e/ /1,4/diazepin-11-he.

Accordingly, the present invention, compounds of General formula (I) can be obtained as described in scheme at the end of the description.

Primary or secondary amines of General formula (II), where R1and R2have the above significance, enter into interaction with halides halogenocarboxylic acids of General formula (III), where X and Y depending on the circumstances, represent a halogen atom, preferably a chlorine atom or bromine, and n has the abovementioned meaning, at temperatures from 0oC up to the boiling point reflux apparatus used solvent, in an inert organic solvent or in a two-phase mixtures of solvents, such as water/toluene water/cyclohexane or water/diethyl ether in the presence of acid acceptors, such as, for example, potassium carbonate or a tertiary amine, to obtain the amides of General form is of suitable solvents, for example, ethers like dioxane or tetrahydrofuran; aromatic hydrocarbons as benzene, toluene or xylene; halogenated aliphatic or aromatic hydrocarbons like chloroform, 1,2-dichloroethane, carbon tetrachloride or chlorobenzene; aliphatic hydrocarbons like cyclohexane or heptane; or dipolar aprotic solvents, such as dimethylformamide, acetonitrile or dimethyl sulfoxide.

Compounds of General formula (IV) enter into interaction with the diamines of General formula (V), and R4, R5and m have the abovementioned meaning, in inert solvents, in the presence of acid acceptors, such as, for example, potassium carbonate, or tertiary amines, or preferably in excess of the diamine of General formula (V) collector WELL.

As inert solvents are suitable, for example, alcohols, like ethanol, n-propanol or isopropanol; ethers like dioxane or tetrahydrofuran; aromatic hydrocarbons as benzene, toluene or xylene; halogenated aliphatic or aromatic hydrocarbons like chloroform, 1,2-dichloroethane, carbon tetrachloride or chlorobenzene; aliphatic hydrocarbons like cyclohexane or heptane; or dipolar aprotic rastvoritelya invention is as a solvent used an excess of the compounds of formula (V).

Upon receipt of the compounds of the formula (VI) temperature can be changed in a wide range from room temperature up to 150oC.

Compounds of General formula (VI) enter into interaction with the halides of carboxylic acids or halides, sulphonic acids of General formula (VII) or (VIII), where R3has the above meaning and X denotes a halogen atom, preferably a chlorine atom or bromine, in an inert solvent without additives or in the presence of an acid acceptor, to obtain the target compounds of General formula (I), where R1, R2, R3, R4, R5and "n" and "m" have the above meaning.

As acid acceptors suitable, for example, carbonates of alkali metals, carbonates of alkali metals or tertiary organic amines as triethylamine, pyridine or N,N-dimethylaniline.

As inert solvents can be used, for example, ethers like dioxane or tetrahydrofuran; aromatic hydrocarbons as benzene, toluene or xylene; halogenated aliphatic or aromatic hydrocarbons like chloroform, 1,2-dichloroethane, carbon tetrachloride or chlorobenzene; formamid, acetonitrile or dimethyl sulfoxide.

Upon receipt of the compounds of formula (I), the temperature can vary from -5oC to +120oC.

To obtain physiologically acceptable salts accession acids, amides aminocarbonyl acids of General formula (I) enter into interaction with inorganic or organic acids as hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, oxalic acid, tartaric acid, citric acid, fumaric acid, maleic acid, lactic acid or succinic acid.

The invention relates also to pharmaceutical compositions containing as active ingredient at least one compound of General formula I or its physiologically acceptable salt is an acid accession and inert pharmaceutically acceptable carriers and excipients such as sucrose, lactose, polyvinylpyrrolidone, methyl cellulose, MCC (microcrystalline cellulose), gelatin, stearates of calcium, or magnesium, calcium disubstituted phosphate, talc, etc. that make up the rest of the song. Methods of obtaining these songs are traditional and is RME salts with physiologically acceptable acid can be administered orally, parenteral, intravenous or percutaneous.

As input forms is therefore suitable in particular tablets, coated tablets, capsules, plasters, solutions, capsules or candles. They can prepare a well-known and conventional in the pharmaceutical practice methods.

The dosage of the pharmaceutical compositions depends on the age, condition and weight of the patient, as well as from the input form. As a rule, the daily dose of biologically active substances with intravenous administration is 0.01-10 mg/kg, and for oral use is 0.1 to 25 mg/kg body weight.

Proposed according to the invention compounds of General formula (I) represent a new antiarrhythmic agent, particularly class III according to Vaughan-Williams (J. Clin. Pharmacol. 24,129-147 (1984). They largely depending on dose lengthen the refractory phase (see tab. 1) and simultaneously extend the duration of the action potential (see tab. 2) in the case of stimulated isolated papillary muscle (heart) Guinea pigs (table. 1-3 refer to the end of the description).

Compounds of General formula (I) upon stimulation with 1 Hz prolong the effective refractory phase (PDE) in a stronger extent than the comparative substance Sematilide, show veii (stimulation with 3 Hz) increases the impact on the effective refractory phase at the same test concentration. Along with these new compounds possess useful (use dependence) properties, while in the case of d/I-Sotalol and Sematilide are the opposite of useful properties. In the treatment of rhythm disorders type of tachycardia new compounds are particularly effective, while the comparative substance - Sematilide and d/I-Sotalol - type arrhythmias tachycardia show only a weak effect.

Impacts of proposed according to the invention compounds of General formula (I) on the potential duration (APD90) are given in table. 2.

New compounds cause a dose-dependent and significant lengthening of APD90without changing significantly the time of the outpouring of blood from one chamber of the heart to another and the maximum speed of the coating.

Impact upon stimulation with 1 Hz is greater than the impact of comparative drugs Sotalol and Sematilide.

Studies in vivo in awake cats show that after oral administration of QT - time ECG strongly and for a long period is lengthened. Test method for impact in oral introduction in the case of awake cats describes Poppe N. and others, PHARMAZIE, 40(12), 857-61 (1985).

New connections so p is knogo rhythm.

Compounds of General formula (I) are strongly antifibrillatory effective. They raise the threshold for ventricular fibrillation cardiac cats are clearly stronger than the comparative substance Lidocaine antiarrhythmic agent of class I. the Compound according to example 8 in a dose of 2.4 mg/kg intravenously causes 6,7 - a 10 - fold increase in the threshold for ventricular fibrillation of the heart, while Lidocaine at a dose of 5.0 mg/kg intravenously increases the threshold of ventricular fibrillation of the heart in 2-2,5 times. The method of determining the threshold of ventricular fibrillation of the heart in the case under anesthesia cats describes Kaverina N. In. and others, PHARMAZIE, 40 (12), 840-844 (1985).

A further significant advantage of the proposed invention the new compounds is clearly greater therapeutic breadth of activity compared with the comparative substances of class I, as Lidocaine Quinidine. As shown in the table. 3, therapeutic index of the compounds according to example 8 is 167, while Quinidine has an index of 11.3 and Lidocaine has an index of 5.0. therapeutic index (TI) calculated from the private by dividing the 50% lethal dose (LD50in the case of rats when administered intravenously at 50% effective dose (ED50) in adults for the economic effect on the arrhythmia due Aconitine in the case of awake rats and determination of acute toxicity in the case of rats describes Sinoway 3.P. and others, CARDIOLOGY, 26(8), 24-28 (1986).

The prolongation of the effective refractory phase and duration of the action potential is determined as follows.

Determination of the effective refractory phase in isolated papillary muscle of the Guinea pig (right ventricle)

Male or female Guinea pigs weighing approximately 400 g death blow to the neck and bleed. Heart quickly removed and fixed in preprofile tub through which bubbled Carbogen. After disclosure of the right ventricle of the heart dissect the papillary muscle (diameter 1 mm) and immediately contribute to the building of a bath (bath volume 39 ml), which is the solution of Krebs-Henseleit of the following composition (data in mmol/l): NaCl = 113,8; CaCl2= 3,2; NaHCO3= 25,0; MgSO4= 1,2; KCl = 4,7; KH2PO4= 1,2; glucose = 10,0. The solution has a temperature of 35oC and continuously purged with a gas mixture of 95% oxygen and 5% CO2. After hanging in the trough body papillary muscle load load 2 mn (=0.2 g). Papillary muscles irritate through bipolar platinum electrodes using pacemaker "TUR RS 21". Records of measured values is carried out using linear meter (Linearcorder) mark VII. The threshold stimulation ( 0.5 MS, dual and constant support throughout the duration of the test. After an adaptation period of 60-90 minutes of exercise defining refractory phase in a standardized stimulation program (separate irritation). The interval between the baseline irritation and extrastimulation after each hit (push) is automatically incremented each with a value of 2 MS until the effective refractory phase. The effective refractory phase is defined as the smallest interval between the baseline irritation and extrastimulation (MS), which shall result in a measurable reduction. After determining baseline values carried out the introduction of the tested substances in the liquid bath. After the exposure time to 1 hour again determine the effective refractory phase.

Assessment is made in percents, and basic value is equal to 100%. Of 3-6 separate values when one of the tested concentrations calculated average values with standard deviation. Average values of 3-4 subjects, concentrations are used for calculation of the effective concentration that causes a 20% elongation effective refractory phase (EC20mol/l). The calculation carried out posredstvennoj papillary muscle of the Guinea pig

Male or female Guinea pigs weighing approximately 400 g death blow to the neck and bleed. Heart quickly remove and dissect thin right papillary muscle. Then the papillary muscle bring into the camera equipment Steiert (Hugo-Sachs Electronik KG), through which a continuously flowing solution of Krebs-Henseleit. The velocity of the flowing of the solution is 18 ml/min solution Composition of Krebs-Henseleit in mmol/l: NaCl = 113,9; CaCl2= 3,2; KH2PO4= 1,2; KCl = 4,7; MgSO4= 1,2; glucose = 10,0. the pH-Value is set equal to 7.4 with NaHCO3. The solution has a temperature of 35oC and continuously purged with a gas mixture of 95% oxygen and 5% CO2.

The papillary muscle is placed on a bipolar electrode (Ag-AgCl. The irritation threshold (mV) is determined at a frequency of 1 Hz. During continuous stimulation at 1 Hz, 3 Hz, and the double threshold irritation adaptation time is 1 hour. The width of the rectangular pulse is 1 MS (milliseconds). Action potentials set by using glass microelectrodes (Kwik - Fil TM, K-series capillaries made of borosilicate glass, Sarasota, Florida 34240), which is filled with 3 mol/l KCl and have a maximum resistance 10-25 Megohm. The signals are amplified with pomodorino analyzer, United with dot matrix printing device. Define the parameters: RP (electrical resting potential/mV/); OV (potential deviations from the set value /mV/); Vmax(the maximum speed of the coating [volume/sec.]); tUe (the time of the outpouring of blood from one chamber of the heart to another /milliseconds/); and APD90(the duration of the action potential at 90% repolarization /milliseconds/).

The evaluation of the actions of substances carried out after the exposure time to 1 hour in superfusion environment compared with the reference value. Calculation of percentage deviation (%) carry out because of the percentage changes for individual experiments (n) compute the mean values and standard deviation (S). Significant changes (p<0,05) are indicated by the sign*.

Examples of implementation

Example 1: /(4-Acetylamino-benzenesulfonyl)-(2-diethylamino-ethyl) - amino/-N, N-DICYCLOHEXYL-ndimethylacetamide-oxalate

10.2 g (0.03 mol) of N,N-DICYCLOHEXYL-2-(2-diethylamino-ethylamino)-ndimethylacetamide dissolved in 200 ml of toluene. In the obtained solution under stirring suspended 5.5 g (0.04 mol) of potassium carbonate (mark H. D. A.). While cooling, make at t=0-5oC, for 10 minutes servings of 12.0 g (0.05 mol) of N-acetyl-sulfanilyl next 4 hours. The liquid phase is decanted, stuck to the walls of the flask oil is stirred with 200 ml of toluene and 100 ml of water for approximately 2 hours at 50oC as long, until everything goes into solution. The combined toluene phase is additionally extracted by shaking with 300 ml of water, then extracted by shaking with 150 ml of 10% hydrochloric acid, and toluene phase is additionally extracted by shaking with 200 ml of water. Hydrochloric acid phase and the last aqueous phase together with stuck to the bottom of the flask of oil mixed with 300 ml of toluene and using 10% sodium hydroxide solution set pH 13-14. After vigorous shaking, the phases are separated, the toluene phase is dried over sodium sulfate and distilled in vacuum to dryness. The residue is brought to a constant weight and dissolved in a small amount of absolute ethanol under heating. To this solution at 50-60oC add a saturated solution of equimolar amount of oxalic acid in absolute ethanol. After cooling and after the crystallization of the obtained crystals are sucked off and recrystallized from ethanol with the addition of approximately 0.2 g of active charcoal. Yield: 8.7 g (44,5% of theory). So pl. 103,5-106oC.

C28H46N4O4,19; H 7,52; N 8,18; S 4,91.

Getting the original product:

N,N-DICYCLOHEXYL-2-(2-diethylamino-ethylamino)ndimethylacetamide

78 g (0.3 mol) of 2-Chloro-N,N-dicyclohexylamine and 174,3 g (1.5 mol) of N, N-diethylethylenediamine in 400 ml of cyclohexane for 10 hours, refluxed, then cyclohexane and excess amine is distilled off in vacuum. The residue is treated with 1 l of water, set in the resulting solution to pH 12 with sodium hydroxide solution, extracted twice with 500 ml of toluene and the combined toluene phases are extracted twice by shaking with water, taking each time with 250 ml of water, dried over sodium sulfate, filtered and distilled in vacuum to dryness.

Output: 100,5 g (99% of theory).

C20H39N3O (mass mole 337,55)

calculated, %: C 71,16; H 11,64; N 12,45;

found, %: C 71,47; H 11,65; N 12,14.

Oxalate: C20H39N3O1,5 C2H2O4(mass mole 472,60)

So pl. = 205-215oC

calculated, %: C 58,45; H of 8.95; N 8,89;

found,%: C 57,21; H 9,00; N 8,90.

N,N-Dicyclohexylcarbodimide

To the mixture 108,8 g (0.6 mol) of dicyclohexylamine in 600 ml of dichloromethane and 122 g (0.88 mol) of potassium carbonate in 160 ml of water, with stirring and at a temperature of 15-20matney temperature. The dichloromethane solution is twice extracted by shaking with 300 ml of water. Dichloromethane is distilled and the residue will recrystallized from isopropanol. Output: of 120.5 g (78% of theory).

So pl. = 111-112oC.

C14H24ClNO:

calculated, %: C 62,35; H 8,07; N 9,86;

found, %: C 62,21; H of 8.09; N, 10,16.

Example 2: N-(DICYCLOHEXYL-carbamoylmethyl)-N-(2-diethyl-amino-ethyl)-3-methoxy-4-nitro-benzamide-oxalate

6,76 g (0.02 mol) of N,N-DICYCLOHEXYL-2-(2-diethylamino-ethylamino)-ndimethylacetamide dissolved in 50 ml of N,N-dimethylformamide. Under stirring and cooling in a water bath in the resulting solution portions contribute to 4.33 g (0.02 mol) of 3-methoxy-4-nitro-benzoyl chloride and stirred at room temperature for 14 hours. After that add 130 ml of cyclohexane and 70 ml of water, the phases are separated and the aqueous phase was concentrated in vacuo to dryness. The residue is partitioned between 100 ml of water and 150 ml ethyl acetate, set pH 13-14, the phases are separated and the organic phase is twice additionally extracted by shaking with water, taking each time 50 ml of water. After drying over sodium sulfate and mixing with 0.2 g of active charcoal is filtered off, the ethyl acetate is distilled off in vacuum, the residue is dissolved in a mixture of toluene with methanol the functions concentrated to dryness, the residue is brought to a constant weight and dissolved in 50 ml of absolute ethanol. To the resulting final solution when heated, add a solution of equimolar amount of oxalic acid in 10 ml of absolute ethanol, concentrated to dryness, the residue is stirred with a mixture of 30 ml of anhydrous acetone and 30 ml of cyclohexane, is sucked off and washed with acetone. The product is dried for 4 hours at 100oC. Yield: 2.6 g (21.4% of theory). So pl. = 183-187oC.

C28H46N4O6C2H2O4(mass mole 606,708)

calculated, %: 59,39; H of 7.64; N 9,23;

found, %: C 59,45; H of 7.64; N 9,07.

Example 3: Cyano-N-(DICYCLOHEXYL-carbamoylmethyl)-N-(2-diethylamino-ethyl)-benzamide-oxalate

of 7.4 g (0.02 mol) of N,N-DICYCLOHEXYL-2-(2-diethylamino-ethylamino)-ndimethylacetamide dissolved by heating in 200 ml of acetonitrile. Under stirring and at room temperature the resulting solution was first portions contribute 2.8 g (0.02 mol) of potassium carbonate (mark H. D. A.), then of 3.31 g (0.02 mol) of 4-cyanobenzaldehyde and within 12 hours with stirring and refluxed. The acetonitrile is distilled off, the residue is partitioned between 300 ml of water and 400 ml of toluene, using ammonia establish a pH of 9-10, the phases are separated and toluol is shivani with 0.2 g of active charcoal, the toluene is distilled off to dryness, the residue is dissolved by heating in 50 ml of absolute ethanol, filtered off and add a solution of equimolar amount of oxalic acid in 10 ml of absolute ethanol. Then concentrate to dryness and the residue "is boiled in 50 ml of cyclohexane, stirred for 2 hours, sucked off and washed with cyclohexane,

Yield: 2.2 g (20% of theory). So pl. = 173-181oC.

C28H42N4O2C2H2O4(mass mole 556, 69)

calculated, %: C 64,72; H of 7.97; N 10,06;

found, %: C 64,75; H 8,29; N 9,75.

Example 4: 4-Chloro-N-(DICYCLOHEXYL-carbamoylmethyl)-N-(2-diethylamino-ethyl)-3-nitro-benzamide-oxalate

6.75 g (0.02 mol) of N,N-DICYCLOHEXYL-2-(2-diethylamino-ethylamino)-ndimethylacetamide dissolved in 50 ml of N,N-dimethylformamide. Under stirring and cooling the resulting solution make portions 4,84 g (0,022 mol) 4-chloro-3-nitro-benzoyl chloride and stirred for 6 hours at room temperature. Then add 150 ml of cyclohexane and 150 ml of water, the phases are separated and the aqueous phase was concentrated in vacuo to dryness. The residue is partitioned between 100 ml of water and 150 ml ethyl acetate, set pH 13-14 with sodium hydroxide solution, the phases are separated and the organic phase is additionally extracted by shaking dvaid the m ethyl acetate is distilled off in vacuum, the residue is dissolved in 10 ml of absolute ethanol and when heated, add a solution of equimolar amount of oxalic acid in absolute ethanol. After crystallization formed is sucked off the crystals and wash them with 10 ml of absolute ethanol. Yield: 5.0 g (41% of theory). So pl. = 174-178oC.

C27H41ClN4O4C2H2O41,5 H2O (mass mole 685,888)

calculated, %: C 63,04; H 8,96; N 8,17;

found, %: C 63,13; H 9,16; N 8,17.

Getting the original product:

N,N-DICYCLOHEXYL-2-(3-dibutylamino-propylamino)-ndimethylacetamide

to 25.3 g (0.1 mol) of 2-Chloro-N,N-DICYCLOHEXYL-ndimethylacetamide and 90.3 g (0.5 mol) of 3-dibutylamino-1-Propylamine in 200 ml of cyclohexane is refluxed for 10 hours, then cyclohexane and excess amine is distilled off in vacuum. The residue is mixed with 200 ml of water and 150 ml of toluene, set pH 11-12 with ammonia or sodium hydroxide solution and stirred for 30 minutes, until the oil phase does not dissolve. The phases are separated, the aqueous phase is additionally extracted by shaking with toluene, taking each time in 70 ml of toluene and the combined toluene phases are extracted by shaking with 80 ml of water, toluene UB>H49N3O (mass mole 407,69)

calculated, %: C to 73.65; H 12,11; N 10,31;

found, %: C 73,73; H 12,09; N 10,33.

Example 7: N-/5-(DICYCLOHEXYL-carbarnoyl)pencil/-N-(2-diethylamino-ethyl)-4-nitro-benzamide-oxalate

9,85 g (0,025 mol) of Dicyclohexylamine 6-(2-diethylamino-ethylamine)-hexanoic acid and 5.56 g (0.03 mol) of 4-nitrobenzylamine in 200 ml of toluene is injected into the interaction as in example 2.

Yield: 14.5 g (91% of theory). So pl. = 125-129oC.

C31H50N4O4C2H2O42H2O (mass mole 638,818)

calculated, %: C 62,04; H 8,83; N 8,77;

found, %: C 62,43; H by 8.22; N 8,73.

Getting original products:

Dicyclohexylamine 6-bromo-hexanoic acid

To a mixture of 275 ml of dichloroethane and of 38.1 g (0,275 mol) of potassium carbonate, dissolved in 220 ml of water, add 50 g (0,275 mol) of dicyclohexylamine and then, under stirring and cooling for 15 minutes was added dropwise and 71.4 g (0.33 mol) of acid chloride of 6-bromo-hexanoic acid. After stirring for 7 hours at room temperature, the phases are separated, the organic phase is extracted twice by shaking with 110 ml of water, dried over sodium sulfate for 30 minutes, mixed with about 2 g of active charcoal, ottilia make 250 ml of cyclohexane. After stirring for 3 hours the precipitation is sucked off and dried. Output: 48,8 g (50% of theory). So pl. = 70,5-73,5oC.

C13H32BrNO (mass mole 358,36)

calculated, %: C 60,32; H 9,00; N 3,91; Br 22,30;

found, %: C 60,23; H 9,11; N Was 4.02; Br 22,39.

Dicyclohexylamine 6-(2-diethylamino-ethylamine)-hexanoic acid

a 35.8 g (0.1 mol) of Dicyclohexylamine 6-bromo-hexanoic acid and to 58.1 g (0.5 mol) of N,N-diethylethylenediamine in 200 ml of toluene is stirred for 72 hours at room temperature. Then add 100 ml of water and 4.4 g of sodium hydroxide. Stirred for 1 hour, the phases are separated and the organic phase is extracted twice by shaking with 100 ml of water. The organic phase is dried over sodium sulfate and stirred for approximately 2 g of active charcoal, filtered, the toluene and the excess amine is distilled off in vacuum. Output: 38,2 g (97% of theory)

C24H47N3O (mass mole 393,64)

calculated, %: C 73,22; H a 12.03; N 10,67;

found, %: C 73,07; H 12,21; N 10,47.

Example 8: N-(DICYCLOHEXYL-carbamoylmethyl)-N-(3-diethylamino-propyl)-4-nitro-benzamide

12.8 g (0.05 mol) of 2-Chloro-N,N-DICYCLOHEXYL-ndimethylacetamide and 32.6 g (0.25 mol) of 3-diethylamino-1-Propylamine in 100 ml of benzene is refluxed config ammonia solution, and N,N-DICYCLOHEXYL-2-(3-diethylamino-propylamino)-ndimethylacetamide extracted with benzene. The benzene solution is shaken out with water and then the benzene is distilled off. The output of oily N,N-DICYCLOHEXYL-2-(3-diethylamino-propylamino)ndimethylacetamide is 16.2 g (92% of theory).

7,03 g (0.02 mol) of N,N-DICYCLOHEXYL-2-(3-diethylamino-propylamino)-ndimethylacetamide dissolved in 70 ml of benzene, mixed with 4.2 g (0.04 mol) of sodium carbonate and with stirring and at room temperature was added dropwise a solution of 5.6 g (0.03 mol) of p-nitro-benzoyl chloride in 30 ml of benzene. The reaction mixture is stirred for 8 hours at room temperature, mixed with 100 ml of water and stirred for further 4 hours at room temperature. Then the benzene solution is separated, extracted by shaking with water, the desired product is extracted from the benzene phase with diluted 1:5 hydrochloric acid, alkalinized using diluted 1: 5 aqueous ammonia and extracted with benzene. After washing the benzene phase with water, the benzene is distilled off. The remainder will recrystallized from 70% aqueous ethanol. Output: 6,21 g (62% of theory). So pl.: = 121-122oC.

C28H44N4O4< / BR>
calculated, %: C 67,17; H 8,86; N 11,19;

found, %: C 69,94; H 8,91; N 11,47.

To restlet solution of 1.26 g (0.01 mol) of oxalic acid dihydrate in 5 ml of ethanol and the mixture is left to stand in the refrigerator. The precipitate is filtered off and recrystallized from ethanol.

Yield: 4.9 g (86,3% of theory).

So pl. = 183,5-185oC.

C28H44N4O40,75 (COOH)2:

calculated, %: C 62,35; H 8,07; N 9,86;

found, %: C 62,21; H of 8.09; N, 10,16.

Example 9: N-(DICYCLOHEXYL-carbamoylmethyl)-N-(3-dimethylamino-propyl)-4-nitro-benzamide-hydrochloride-hydrate

To a solution of 7.2 g (0,022 mol) of N,N-DICYCLOHEXYL-2-(3-dimethylamino-propylamino)ndimethylacetamide in 60 ml of benzene is added 4.8 g (0.045 mol) of sodium carbonate and with stirring and at room temperature was added dropwise a solution of 6.1 g (0,033 mol) of 4-nitro-benzoyl chloride in 30 ml of benzene. The reaction mixture is stirred 6 hours at room temperature, mixed with 100 ml of water and stirred at room temperature for 4 hours. The benzene solution is separated, extracted by shaking with water and the desired product extracted from the benzene phase with diluted 1:5 hydrochloric acid. Hydrochloric acid phase is alkalinized with dilute ammonia solution and extracted with benzene. After washing the benzene phase with water, the benzene is distilled off, the residue is dissolved in anhydrous ether and added dropwise a solution of gaseous HCl in ethyl acetate. Dropped osado the/P>C26H40N4O4HCIH2O

calculated, %: C 59,24; H by 8.22; N 10,63; Cl 6.73 x; H2O 3,4;

found, %: C 59,52; H 8,35; N 10,91; CI 7,01; H2O 3,7.

Example 10: N-(DICYCLOHEXYL-carbamoylmethyl)-N-(3-diethylamino-propyl)-2-nitro-benzamide-oxalate

3.51 g (0.01 mol) of N,N-DICYCLOHEXYL-2-(3-diethylamino-propylamino)-ndimethylacetamide dissolved in 40 ml of benzene, mixed with a 2.12 g (0.02 mol) of sodium carbonate and with stirring and at room temperature was added dropwise a solution of 2.8 g (0.015 mol) of 2-nitro - benzoyl chloride in 10 ml of benzene. The reaction mixture is stirred for 6 hours at room temperature, mixed with 60 ml of water and stirred for further 4 hours at room temperature. The benzene solution is separated, shaken with water and the desired product extracted from the benzene phase with diluted 1:5 hydrochloric acid. Hydrochloric acid phase is alkalinized using diluted 1:5 aqueous ammonia and extracted with benzene. After washing the benzene phase with water, the benzene is distilled off. The remainder of 4.2 g) was dissolved in 8 ml of isopropanol, then add a solution of 0.82 g (0,009 mol) of oxalic acid in 7 ml of isopropanol and a small amount of ether and kept in the refrigerator until crystallization. The precipitation is filtered off and N4O4(COOH)2:

calculated, %: C 61,00; H a 7.85; N 9,48;

found, %: C 61,35; H 7,86; N 9,74.

Example 11: N-(DICYCLOHEXYL-carbamoylmethyl)-N-(3-diethylamino-propyl)-3-nitro-benzamide-oxalate

7,03 g (0.02 mol) of N,N-DICYCLOHEXYL-2-(3-diethylamino-propylamino)-ndimethylacetamide, of 4.2 g (0.04 mol) of sodium carbonate and 5.6 g (0.03 mol) of 3-nitro-benzoyl chloride in benzene is injected into the interaction analogously to example 10.

The residue (8.5 g) was dissolved in 15 ml of isopropanol, mixed with 2.4 g (0.019 mol) of oxalic acid dihydrate dissolved in 8 ml of isopropanol, add 3 ml of ether and the solution is left to stand in the refrigerator. The precipitation is filtered off and recrystallized from isopropanol and ether.

Yield: 7.5 g (63,5% of theory). So pl. = 145-146oC.

C28H44N4O4(COOH)2:

calculated, %: C 61,00; H a 7.85; N 9,48;

found, %: C 61,06; H 7,87; N 9,67.

Example 12: N-(DICYCLOHEXYL-carbamoylmethyl)-N-(2-diethylamino-ethyl)-4-nitro-benzamide

13.5 g (0.04 mol) of N,N-DICYCLOHEXYL-2-(2-diethylamino-ethylamino)ndimethylacetamide, and 8.4 g (0.08 mol) of sodium carbonate and 11.1 g (0.06 mol) of 4-nitro-benzoyl chloride is injected into the interaction analogously to example 10. The remainder will recrystallized from 70% aqueous ethanol. Yield: 10.2 g (52.3% of the 64; H 8,7; N 11,51;

found, %: C 67,02; H 8,6; 11,77.

Example 13: N-(DICYCLOHEXYL-carbamoylmethyl)-N-(3-morpholine-4-yl-propyl)-4-nitro-benzamide

N,N-DICYCLOHEXYL-2-(3-morpholine-4-yl-propyl)-ndimethylacetamide get analogously to example 8 from 2-chloro-N,N-dicyclohexylurea of tumida and 3 morpholino-1-Propylamine.

of 9.1 g (0,025 mol) of N,N-DICYCLOHEXYL-2-(3-morpholine-4-yl-propyl)ndimethylacetamide, with 5.3 g (0.05 mol) of sodium carbonate and 7.5 g (0.04 mol) of 4-nitro-benzoyl chloride is injected into the interaction analogously to example 10. The residue (11.5 g) was dissolved by heating in 25 ml of ethanol and left to stand for several days. The precipitation is sucked off and recrystallized from ethanol. Yield: 7.8 g (60,6% of theory).

So pl. = 153-154oC.

C28H42N4O5:

calculated, %: C 65,34; H 8,23; N 10,87;

found, %: C 62,28; H compared to 8.26; N 11,14.

Example 14: N-(DICYCLOHEXYL-carbamoylmethyl)-4-nitro-N-(2-oxo-2-piperidine-1-yl-ethyl)-benzamide-oxalate

N, N-DICYCLOHEXYL-2-(2-piperidine-1-yl-ethylamino)ndimethylacetamide obtained from 2-chloro-N,N-DICYCLOHEXYL-ndimethylacetamide and 2-piperidinoethyl analogously to example 8.

13,96 g (0.04 mol) of N,N-DICYCLOHEXYL-2-(2-piperidine-1-yl-ethylamino)-ndimethylacetamide, 7.5 g (0.07 mol) of sodium carbonate and 11.1 g (0.06 mol) of 4-nitro-benzoyl the l of ethanol and 30 ml of water). Yield: 11.4 g (55.6% of theory). So pl. = 164-165oC.

C28H42N4O4:

calculated, %: C 67,44; H 8,49; N 11,27;

found, %: C 67,63; H 8,42; N 11,65.

Example 15: N-(Benzyl-methyl-carbamoylmethyl)-N-(2-diethylamino-ethyl)-4-nitro-benzamide hydrochloride

of 19.8 g (0.1 mol) N-Methyl-benzyl-chloracetamide and 32.5 g (0.25 mol) of 3-diethylamino-1-Propylamine in 100 ml of benzene is refluxed for 8 hours. The benzene solution is extracted by shaking with water and the desired product extracted from the benzene phase with 3% hydrochloric acid. Hydrochloric acid phase is alkalinized using diluted 1:3 aqueous ammonia and extracted with benzene. After washing the benzene solution with water, the benzene is distilled off and the residue is distilled in vacuum. Get primarily of 21.5 g (74% of theory) of methylbenzylamine N-(3-diethylaminopropyl)aminouksusnoy acid so Kip. 300-305oC at 3 mm RT.article.

C17H29N3O

calculated, %: C 70,13; H becomes 9.97; N accounted for 14.45;

found, %: C 70,07; H 10,24; N 14,40.

21,5 g (0,074 mol) of Methylbenzylamine N-(3-diethylamino-propyl)-aminouksusnoy acid, 16.3 g (0,154 mol) of sodium carbonate and 18.6 g (0.1 mol) of 4-nitro-seniorhood enter into interaction analogously to example 10. Seadoc sucked off and recrystallized from isopropanol. Yield: 17.8 g (50,4% of theory)

So pl. = 160-162oC.

C24H32N4O4HCl

calculated, %: C 60,43; H 6,97; N 11,75; Cl 7.43;

found, %: C 60,62; H of 7.23; N 11,73; CI 7,50.

Getting the original product:

N-Methyl-N-benzyl-chloracetamide

To a mixture of 30,2 g (0.25 mol) of N-methylbenzylamine in 300 ml of chloroform and 54.4 g (0.4 mol) of potassium carbonate in 80 ml of water, with stirring and at a temperature of 20-25oC for 30 minutes was added dropwise 40.6 g (0.36 mol) of chloroacetanilide. After stirring for 2 hours at room temperature, the chloroform solution is extracted by shaking first with water, then with 3% hydrochloric acid and with water. The chloroform is distilled off and the residue is distilled in vacuum.

Output: 46,7 g (94.5% of theory). So Kip.: 155-158oC at 5 mm RT.article.

C10H12ClNO:

calculated, %: C 60,91; H the 6.06; N 7,10; Cl 17,97;

found, %: C, in comparison with 60.87; H 5,97; N for 6.81; CI 17,94.

Example 16: N-(3-Diethylamino-propyl)-N/2-(10,11-dihydro-dibenzo/b,f/-azepin-5-yl)-2-oxo-ethyl/-4-nitro-benzamide-oxalate

of 27.2 g (0.1 mol) of 2-Chloro-N-(10,11-dihydro-dibenzo/b,f/azepine-5-yl)-ndimethylacetamide and 39 g (0.3 mol) of 3-diethylamino-1-Propylamine is stirred for 3 hours at 100oC, then distilled off excess 3-diethylamino-1-Propylamine phase is extracted by shaking with water and the desired product extracted from the benzene phase with diluted 1: 5 hydrochloric acid. Hydrochloric acid phase is alkalinized using diluted 1:5 aqueous ammonia and extracted with benzene. After washing the benzene phase with water, the benzene is distilled off. The yield of 2-(3-diethylamino-propylamino)-N-(10,11-dihydro-dibenzo-/b, f/azepine-5-yl)-ndimethylacetamide is 33 g (90% of theory).

14,61 g (0.04 mol) of 2-(3-diethylamino-propylamino)-N-(10,11-dihydro-dibenzo/b, f/azepine-5-yl)-ndimethylacetamide dissolved in 200 ml of benzene, the resulting solution contribute to 8.4 g (0.08 mol) of sodium carbonate and with stirring and at room temperature was added dropwise a solution of 11.1 g (0.06 mol) of 4-nitro-benzoyl-chloride in 50 ml of benzene. The reaction mixture is stirred for 5 hours at room temperature, then mixed with 150 ml of water and stirred for further 4 hours at room temperature. The benzene phase is separated, shaken with water and the benzene is distilled off. The output of oily N-(3 - diethylamino-propyl)-N/2-(10,11-dihydro-dibenzo/b, f/azepine-5-yl)-2-oxo-ethyl/-4-nitro-benzamide is 19,75 g (95% of theory).

To a solution of 10.3 g (0.02 mol) of N-(3-diethylamino-propyl)-N/2-(10,11-dihydro-dibenzo/b, f/azepine-5-yl/-2-oxo-ethyl/-4-nitro-benzamide in 100 ml isopropanol added a solution of 2.8 g (0,022 mol) of oxalic acid dihydrate in 100 ml of 50% isopropanol and allowed to stand in holodilniki-210oC.

C30H34N4O4(COOH)2:

calculated, %: C 63,56; H of 6.02; N 9,26;

found, %: C 63,57; H 6,23; N 9,52.

Example 17: 4-Amino-N-(DICYCLOHEXYL-carbamoylmethyl)-N-(3 - diethylamino-propyl) benzamide - oxalate hydrate

5 g (0.01 mol) of N-(DICYCLOHEXYL-carbamoylmethyl)-N-(3-diethylamino-propyl)-4-nitro-benzamide in 50 ml of methanol with the addition of 0.3 g of palladium-on-coal (10% Pd) hydronaut under stirring and at room temperature. theoretical amount of hydrogen is absorbed within 2 hours. The reaction mixture is stirred for 3 hours in an atmosphere of hydrogen, the catalyst is filtered off and the methanol is distilled off.

Oily 4-amino-N-(DICYCLOHEXYL-carbamoylmethyl)-N-(3-diethylamino-propyl)-benzamide (4.7 g) was dissolved in 30 ml of absolute ethanol and mixed with a solution of 2.5 g (0.02 mol) of oxalic acid in 15 ml of absolute ethanol. The ethanol is distilled off, the residue is dissolved in 40 ml of isopropanol, add a small amount of ether and left to stand in the refrigerator until crystallization. The precipitate is sucked off and dried at 50-60oC in vacuum. Exit; 4.1 g (66% of theory). So pl.=90,5-92oC.

C28H46N4O21,5 (COOH)2H2O

calculated, %: C 59,64; H 8,24; N 9, carbamoylmethyl)-N-(3-diethyl-amino-propyl)benzamide-hemihydrate

To a solution of 4.7 g (0.01 mol) 4-amino-N-(DICYCLOHEXYL-carbamoylmethyl)-N-(3-diethylaminopropyl)benzamide in 40 ml of anhydrous benzene is added a solution of 5.1 g (0.05 mol) of acetic anhydride in 10 ml of anhydrous benzene. The temperature rises to 45oC. the Reaction mixture for 6 hours refluxed. Benzene and acetic anhydride is distilled off. To the residue (5 g) add water and dilute hydrochloric acid and the solution is poured into a dilute solution of ammonia. The precipitate is filtered off, washed with diluted ammonia solution and water and dried in vacuum. Yield: 3.8 g (74% of theory.). So pl. = 92-93oC.

C30H48O3N40,25 H2O

calculated, %: C 69,66; H 9,45; N 10,85; H2O 0,87;

found, %: C 69,28; H 9,4; N 10,81; H2O 0,73.

Example 19: 4-Acetylamino-N-(DICYCLOHEXYL-carbamoylmethyl)-N-(2-diethyl-amino-ethyl)-benzamide-oxalate

4-Amino-N-(DICYCLOHEXYL-carbamoylating)-N-(2-diethylamino-ethyl)-benzamide obtained from N-(DICYCLOHEXYL-carbamoylmethyl)-N-(2 - diethylamino-ethyl)-4-nitro-benzamide according to the procedure of example 17.

To a solution of 4.57 g (0.01 mol) 4-amino-N-(DICYCLOHEXYL-carbamoylmethyl)-N-(2-diethylamino-ethyl)-benzamide in 40 ml of benzene is added a solution of 5.1 g (0.05 mol is 6 hours and then concentrated to dryness. The residue is dissolved in water, alkalinized using diluted 1:5 aqueous ammonia and extracted with benzene. After washing the benzene phase with water, the benzene is distilled off.

The residue (4.9 g) was dissolved in 10 ml of isopropanol, add a solution of 1.26 g (0.01 mol) of oxalic acid dihydrate in 15 ml of isopropanol and allowed to stand until crystallization. The precipitate is sucked off and recrystallized from isopropanol.

Output: Android 4.04 g (68,6% of theory)

So pl. = 195-197oC.

C29H46N4O3(COOH)2:

calculated, %: C 63,24; H by 8.22; N 9,52;

found, %: C 63,32; H 8,44; N 9,66.

Example 20: 4-Acetylamino-N-(benzyl-methyl-carbamoylmethyl)-N-(3 - diethyl-amino-propyl)-benzamide-hydrate

4-Amino-N-(benzyl-methyl-carbamoylmethyl)-N-(3-diethylamino-propyl)-benzamide obtained from N-(benzylmethyl-carbamoylmethyl)-N-(3-diethylamino-propyl)-4-nitro-benzamide according to the procedure of example 17.

5.9 g (0,0143 mol) 4-Amino-N-(benzyl-methyl-carbamoylmethyl)-N-(3-diethylamino-propyl)benzamide and was 7.45 g (0,073 mol) of acetic anhydride in 50 ml of benzene is refluxed for 6 hours and then distilled to dryness. The residue is mixed with water and 10% aqueous ammonia and extracted with benzene. Benzene Rastogi and leave to stand until crystallization. The precipitate is sucked off and dried in vacuum for 3 hours at a temperature of 30-40oC. Output: 5,22 g (78% of theory). So pl. = 55-56oC.

C26H36N4O3H2O

calculated, %: C 66,33; H 8,14; N 11,90; H2O 3,79;

found, %: C 66,19; H 8,11; N 12,05; H24.20.

Example 21: 4-Carbamaxepine-N-(DICYCLOHEXYL-carbarnoyl-methyl)-N-(3-diethylamino-propyl)-benzamide-oxalate hydrate

4.7 g (0.01 mol) 4-Amino-N-(DICYCLOHEXYL-carbamoylmethyl)- (3-diethylamino-propyl)benzamide are dissolved in 60 ml of benzene, then mixed with a 2.12 g (0.02 mol) of sodium carbonate and with stirring and at a temperature of 15-20oC was added dropwise a solution of 2.16 g (0.02 mol) of ethyl ether of Harborview acid in 10 ml of benzene. The reaction mixture is stirred 3 hours at room temperature, add 50 ml of water and stirred for a further 30 minutes at room temperature. The benzene phase is separated, shaken with water and distilled to dryness. The residue (5.2 g) was dissolved in 20 ml of isopropanol. Add 1 g (to 0.011 mol) of oxalic acid, dissolved in 5 ml of isopropanol and a small amount of water, and leave to stand in the refrigerator until crystallization. The precipitate is sucked off and recrystallized from isopropanol and ether.

Exit>2O

calculated, %: C 61,76; H 8,32; N 8,73; H2O 1,4;

found, %: C 61,60; H 8,40; N 9,01; H2O 2,0.

Example 22: N-(DICYCLOHEXYL-carbamoylmethyl)-N-(3-diethylamino-propyl)-4-methanesulfonamido-benzamid-oxalate

To a solution of 7.1 g (0.015 mol) of 4-amino-N-(DICYCLOHEXYL-carbamoylmethyl)-N-(3-diethylamino-propyl)-benzamide and 3.03 g (0.03 mol) of triethylamine with stirring and at a temperature of 15-20oC add a solution of 2.06 g (0.018 mol) methanesulfonyl-chloride in 10 ml of chloroform. The reaction mixture is stirred for 6 hours at room temperature, then refluxed for 6 hours, add the following 1,72 g (0.015 mol) of methanesulfonamide and refluxed for 6 hours. After cooling, add 50 ml of water and stirred for 2 hours. Then add a solution of 4.8 g (0.035 mol) of potassium carbonate in 20 ml of water and stirred for 3 hours. The chloroform phase is separated and distilled to dryness. The residue is mixed with dilute ammonia solution and extracted with benzene. After washing the benzene phase with water, the benzene is distilled off. The residue is dissolved in 70 ml of methanol and 60 ml of triethylamine and refluxed for 6 hours. Then distilled to dryness, the mod is g) dissolved in 15 ml of ethanol and add a solution of 1.4 g (to 0.011 mol) of oxalic acid dihydrate in 5 ml of ethanol. At the end of crystallization (refrigerator) the precipitate is sucked off and recrystallized from ethanol. Yield: 4.9 g (51% of theory). So pl. = 175-176oC.

C29H48N4O4S(COOH)2:

calculated, %: C 58,27; H 7,88; N 8,77; S 5,02;

found, %: C 58,26; H 7,81; N 9,06; S equal to 4.97.

Example 23: N-(DICYCLOHEXYL-carbamoylmethyl)-N-(3-diethylamino-propyl)-4-methanesulfonamido-benzamid-yodmetilat

2.7 g (0,005 mol) of N-(DICYCLOHEXYL-carbamoylmethyl)-N-(3-diethylamino-propyl)-4-methanesulfonamido-benzamide and 2.13 g (0.015 mol) of iodomethane in 30 ml of acetone is refluxed for 3 hours. After cooling, the precipitate is sucked off and washed with acetone. The residue in 30 ml of acetone is refluxed for 20 minutes, sucked off and recrystallized from isopropanol.

Yield: 2.6 g (76% of theory). So pl. = 139-140,5oC.

C30H51N4SO4< / BR>
calculated, %: C 52,16; H 7,44; N 8,11; S WITH 4.64;

found, %: C 52,49; H of 7.48; N 7,84; S 4,47.

Example 24: N-(DICYCLOHEXYL-carbamoylmethyl)-N-(2-diethylamino-ethyl)-4-methanesulfonamido-benzamid-oxalate

7.0 g (0,0155 mol) 4-Amino-N-(DICYCLOHEXYL-carbarnoyl-methyl)-N-(2-diethylamino-ethyl) - benzamide and 2.7 g (0,0235 mol) of methanesulfonamide enter into mutually-ethyl)-4-methanesulfonamido-benzamid (6,9 g) dissolved in 9 ml of isopropanol, add a solution of 0.4 g (of 0.003 mol) of oxalic acid dihydrate in 2 ml of isopropanol, the precipitation is sucked off and recrystallized from ethanol. Yield: 2.2 g (73.1% of theory).

C28H46N4SO40,5 (COOH)2:

calculated, %: C 60,08; H 8,17; N 9,66; S OF 5.53;

found, %: C 59,79; H 8,14; N 9,58; S 5,56.

Example 25: N-(3-Diethylamino-propyl)-N/2-(3-forfinal-1-yl-amino)-2-oxo-ethyl/-4-nitro-benzamide

3.7 g (0.01 mol) of 2-(3-Diethylamino-propylamino)-N-(3-forfinal)-2HClH2O, 50 ml of chloroform, 2.8 g (0.015 mol) of p-nitro-benzoyl chloride and 2.8 ml (0.02 mol) of triethylamine is refluxed for 2 hours. Over the course of the reaction is monitored by TLC (thin layer chromatography) (toluene: methanol: concentrated solution of NH3= 60:40:1). At the end of the interaction, the reaction mixture was extracted three times with 20 ml of saturated potassium carbonate solution and then twice with 10 ml of concentrated HCl. The combined hydrochloric acid phase is extracted by shaking once with 20 ml of chloroform, alkalinized with concentrated ammonia solution, extracted with twice 20 ml of chloroform and the combined chloroform phase is extracted once with 20 ml of water. The chloroform phases will recrystallized from 5 ml of isopropanol. Yield: 1.9 g (44.2% of theory).

So pl. = 106 - 109oC

C22H27N4O4F (mass mole 430,48)

calculated, %: C 61,38; H 6,32; N 13,02;

found, %: C 61,49; H 6,35; N 13,45.

The original product for the above compounds are synthesized as follows:

2-(3-Diethylamino-propylamino)-N-(3-forfinal)-ndimethylacetamide-dihydrochloride hydrate

3.5 g (0.02 mol) Chloroacetyl-3-fernilee and 13.0 g (0.1 mol) 3-diethylamino-1-Propylamine unite together, and the internal temperature rises to about 50oC. then for 1 hour and stirred at room temperature and the excess amine is distilled off in vacuum. The crystalline residue is mixed with acetonitrile, is heated until complete dissolution and carefully cooled. This solution is passed gaseous HCl until acidic. Hydrochloride partially crystallizes. The reaction mixture was concentrated and the residue will recrystallized from isopropanol.

Yield: 3.4 g (45.8% of theory). So pl. = 174-178oC.

C15H24N3OF2HClH2O (mass mole 372,32):

calculated, %: C 48,51; H 7,50; N 11,31; Cl-KZT 19.09;

found, %: C 48,13; H a 7.62; N 11,33; CI-19,10.

Example 26: N-(3-Diethylam is 022 mol chloroacetaldehyde) dissolved in 30 ml of chloroform, mixed with 3.9 g (0.02 mol) of 4-nitro-benzoyl chloride and boiling under reflux is stirred for 5 hours. Then the reaction mixture is extracted by shaking once with 10 ml diluted 1:1 ammonia solution, once with 10 ml of water and twice with diluted 1:1 HCl. The combined hydrochloric acid phase is extracted once with 10 ml of water, alkalinized with concentrated solution of NH3twice extracted with chloroform, taking each time with 20 ml of chloroform and the combined chloroform phase is extracted by shaking with 10 ml of water. Thereafter, the chloroform phase is dried and concentrated. The crystalline residue (4.7 g) is recrystallized from 5 ml of isopropanol and dried at 70oC. Yield: 2.2 g (39,5% of theory, based on morpholin Chloroacetic acid).

C20H30N4O5(mass mole 406,49)

calculated, %: 59,10; H 7,44; N 13,78;

found, %: C 58,80; H 7,38; N 13,86.

Getting the original product:

2-(3-Diethylamino-propylamino)acetyl-morpholin

13 g (0.1 mol) 3-Diethylamino-1-Propylamine when cooling is mixed with 3.3 g (0,022 mol) of morpholine Chloroacetic acid. The reaction mixture is stirred for 1 hour at room temperature, then oosevelt at 140oC and a pressure of 0.8 to 1 Torr. Get an oily residue, which without further purification used for the subsequent acylation reaction.

Example 27: N-/2-(3-Carbethoxy-amino-10,11-dihydro-dibenzo/b,f/azepine-5-yl)-2-oxo-ethyl/-N-(2-diethylamino-ethyl)-4-nitro-benzamide

8.8 g (0.02 mol) 2-(Diethylamino-ethylamino)-N-/(3-carbethoxy - amino-10,11-dihydro-dibenzo/b, f/azepine)-5-yl/-ndimethylacetamide. 100 ml of toluene and a 9.25 g (0.05 mol) of 4-nitro-benzoyl - chloride is stirred for 1 hour at boiling under reflux. After cooling, the toluene is poured from the spin-off (sudivshegosya) product and the residue treated with chloroform. The chloroform phase is extracted by shaking three times with 20 ml of saturated potassium carbonate solution and once with 20 ml of water. Then dried over sodium sulfate and concentrated. The residue (11.6 g) treated with 20 ml of isopropanol. After some time the product crystallizes. Output: 10.7 g (90,9% of theory).

C32H31N5O6(mass mole 588,69):

calculated, %: C 65,40; H 6,35; N 11,92;

found, %: C 65,36; H 6,34; N 12,18.

Example 28: 8-Chloro-5-{N-[3-(diethylamino)propan-1-yl]-N-(p-methylsulfonylbenzoyl)/aminoacetyl} -5,10-dihydro-11H-dibenzo-/b,e//1,4/diazepin-11-he-0.5 hydrochloride hydrate

2,5 Yes dissolved in 50 ml of water and concentrated solution of ammonia release basis. Then extracted by shaking twice with 25 ml of chloroform and the combined chloroform phase is extracted by shaking with 20 ml of water. The combined chloroform phase is then dried over sodium sulfate, mixed with 0.4 ml (0.005 mol) of pyridine, heated to a temperature bath of 80oC (boiling under reflux), add 1.8 g (0,0075 mol) of 4-methyl-sulfonamidophenylhydrazine and stirred for 3 hours at the boil under reflux. This stands buttery product that is deposited on the edge of the flask. The reaction mixture is then mixed with 20 ml diluted 1: 1 ammonia solution, mix well, separated with a separating funnel, the chloroform phase is again extracted by shaking with 20 ml of water and extracted with diluted 2:1 with hydrochloric acid (at a higher dilution of hydrochloric acid also come to the selection buttery product between phases). Hydrochloric acid phase is again extracted by shaking with 20 ml of chloroform, alkalinized with concentrated ammonia solution and then extracted twice with chloroform, taking each time in 25 ml of chloroform. The combined chloroform phase (50 ml) is shaken now with 30 ml of water, dried over sodium sulfate and g (40%).

C30H34N5O5SClH2O (mass mole 666,63):

calculated, %: C 55,57; H 5,67; N 10,80; Cl 8,20; Cl-2,73;

found, %: C 55,81; H 5,62; N10,90; CI 8,30; CI-2,81;

calculated, %: S 4,95; H2O 2,8.

found, % S 4,96; H2O 2,4.

Example 29: 8-Chloro-5-{ /6-[N-(3-diethylamino)propan-1 - yl]-N-benzoyl/-amino-1-oxohexyl} -5,10-dihydro-11N-dibenzo/b, e//1,4/diazepin-11-he-hydrochloride hemihydrate

5,44 g (0.01 mol) of 8-Chloro-5-{6-/[3-(diethylamino)propan-1-yl]amino/-1-oxohexyl} -5,10-dihydro-11N-dibenzo/b, e/ /1,4/diazepin-11-he-dihydrochloride-hemihydrate is dissolved in 50 ml of water, mixed with kontsetrirovannoe solution of ammonia until strongly alkaline and extracted with 50 ml and 20 ml of toluene. After shaking with 20 ml of water and drying over sodium sulfate to the combined toluene phases, with a bath temperature of 70-80oC and under stirring, add 3.5 g (0,025 mol) of benzoyl chloride. The reaction time is 2 hours. After cooling the reaction mixture, the toluene is poured from the separated oil, the residue is treated by heating 30 ml of isopropanol, the isopropanol again distilled off and the residue is dried under a pressure of 80 mbar (4,2 g of amorphous product). 3.7 g of the substance is dissolved in 35 ml of methanol and purified by HPLC. Protochloride with 0.5 mole of water.

C33H39N4O3Cl0,5 H2O (mass mole 620,63):

calculated, %: C 63,87; H 6,66; N 9,03; Cl 11,43;

found, %: C 64,20; H 6,56; N 9,20; CI 11,27.

Example 30: N-(2-Diethylamino-ethyl)-4-nitro-N-(2-oxo-2-piperidine-1-yl-ethyl)benzamide(COOH)2(mass mole 480,52)

calculated, %: From 54.99; H of 6.71; N 11,66;

found, %: C 55,27; H 6,77; N 11,73.

1. Amides aminocarbonyl acids of General formula I

< / BR>
where R1, R2denote hydrogen; a linear or branched (C1-C8)-alkyl, (C3-C8-cycloalkyl, such as cyclohexyl; phenyl, which can be single or twofold substituted linear (C1-C4)-alkyl, (C1-C2-alkoxyl, halogen, a cyano, a nitro-group, a trifluoromethyl or allmineral; phenylalkyl, where the alkyl chain may contain 1-3 C-atoms and a phenyl ring, which may be single or twofold substituted stands, a methoxy group, halogen, nitro, cyano or arylaminopoly; or

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

< / BR>
where R6may denote H, NHCO2CH2CH3;

R3means CO - R2,

1-C4)-alkyl, (C1-C2-alkoxyl, halogen, cyano-, nitro-group, a trifluoromethyl, sulfonamide, methanesulfonamido or allmineral; phenylalkyl, where the alkyl chain may contain 1-3 C-atoms and the phenyl ring may be single or twofold substituted stands, a methoxy group, halogen, nitro, cyano or arylaminopoly;

R8denotes hydrogen, alluminare;

R4, R5denotes a linear or branched (C1-C6)-alkyl, (C3-C6-cycloalkyl, such as cyclohexyl; phenyl; phenyl-alkyl, where the alkyl group can contain 1-3 C-atoms; or

< / BR>
represents piperidine or morpholine,

n = 1-5;

m = 2-4,

or their physiologically acceptable salts accession acids.

2. Connection on p. 1, representing;

/4-acetylamino-benzazolyl/-/2-diethylamino-ethyl/-amino/-N, N-DICYCLOHEXYL-ndimethylacetamide;

N/DICYCLOHEXYL-carbamoylmethyl/-N-/2-diethylamino-ethyl/-3-methoxy-4-nitro-benzamide;

4-cyano-N-/DICYCLOHEXYL-carbamoylmethyl/-N-diethylaminoethyl/benzamide;

4-chloro-N-/DICYCLOHEXYL-carbamoylmethyl/-N-/2-diethylaminoethyl/-3-nitro-benzamide;

N-/2-dicyclohexylamine-carbamoylmethyl/-N-/3-diameter/-benzamide;

N-/5-(DICYCLOHEXYL-carbarnoyl)pencil/-N-(2-diethylamino-ethyl)-4-nitro-benzamide;

4-amino - N-(DICYCLOHEXYL-carbamoylmethyl)- N-(3-diethylamino-propyl)benzamide;

N-(DICYCLOHEXYL-carbamoylmethyl)-N-(3-diethylamino-propyl)-4-nitro-benzamide;

N-(DICYCLOHEXYL-carbamoylmethyl)-N-(3-diethylamino-propyl)-2-nitro-benzamide;

4 carbamaxepine-N-(DICYCLOHEXYL-carbamoylmethyl)-N-(3-diethylamino-propyl)-benzamide;

N-(DICYCLOHEXYL-carbamoylmethyl)-N-(3-morpholine-4-yl-propyl)-4-nitro-benzamide;

N-(DICYCLOHEXYL-carbamoylmethyl)-N-(3-diethylamino-propyl)-3-nitro-benzamide;

N-(DICYCLOHEXYL-carbamoylmethyl)-N-(3-dimethylamino-propyl)-4-nitro-benzamide;

4-acetylamino-N-(DICYCLOHEXYL-carbamoylmethyl)-N-(3-diethylamino-propyl)-benzamide;

N-(DICYCLOHEXYL-carbamoylmethyl)-N-(2-diethylamino-ethyl)-4-nitro-benzamide;

4-acetylamino-N-(DICYCLOHEXYL-carbamoylmethyl)-N-(2-diethylamino-ethyl)-benzamide;

N-(DICYCLOHEXYL-carbamoylmethyl)-4-nitro-N-(2-piperidine-1-yl-ethyl)benzamide;

4-acetylamino-N-(benzyl-methyl-carbamoylmethyl)-N-(3-diethylamino-propyl)-benzamide;

N-(DICYCLOHEXYL-carbarnoyl)-N-(3-diethylamino-propyl)-4-methanesulfonamido-benzamide;

N-(DICYCLOHEXYL-carbamoylmethyl)-N-(3-diethylamino-propyl)-4-meth is ansamed-yodmetilat;

N-(3-diethylamino-propyl)-N/2-(10,11-dihydro-dibenzo/b, f/azepine-5-yl)-2-oxo-ethyl/-4-nitro-benzamide;

N-(2-diethylamino-ethyl)-4-nitro-N-(2-oxo-2-piperidine-1-yl-ethyl)-benzamide;

N-(benzyl-methyl-carbamoylmethyl)-N-(2-diethylamino-ethyl)-4-nitro-benzamide;

N-(DICYCLOHEXYL-carbamoylmethyl)-N-(2-diethylamino-ethyl)-4-methanesulfonamido-benzamide;

N-(3-diethylamino-propyl)-N/2-(3-forfinal-1-yl-amino)-2-oxoethyl/-4-nitro-benzamide;

N-(3-diethylamino-propyl)-N-(2-morpholine-4-yl-2-oxo-ethyl)-4-nitro-benzamide;

N-/2-(3-carbethoxy-amino-10,11-dihydro-dibenzo/b, f/azepine-5-yl)-2-oxo-ethyl/-N-(2-diethylamino-ethyl)-4-nitro-benzamide;

8-chloro-5 - {N-[3-(diethylamino)propan-1-yl] -N-(p-methylsulfonylamino-benzoyl)-aminoacetyl}-5, 10-dihydro-11H-dibenzo/ b, e//1, 4/diazepin-11-he;

8-chloro-5-{ /6-[N-(3-diethylamino)propan-1-yl] -N-benzoyl/-amino-1-oxo-hexyl}-5,10-dihydro-11N-dibenzo/b, e//1, 4/diazepin-11-he.

3. The method of producing amides aminocarbonyl acids of General formula I, where R1-R5and n and m have the above significance, characterized in that the primary or secondary amines of General formula II,

< / BR>
where R1and R2have the above meaning,

enter into interaction with the halides w-halogencarbonic acids total is the biphasic solvents or mixtures of solvents, in the presence of an acid acceptor to obtain amides of General formula IV

R1R2N-C(O)-(CH2)n-Y

and R1, R2and Y have the above meaning,

and amides then enter into interaction with the diamines of General formula V

< / BR>
and R4and R5have the above meaning,

in inert solvents, in the presence of an acid acceptor to obtain compounds of General formula VI

< / BR>
where R1, R2, R4and R5and n and m have the abovementioned meaning,

and translate them using halides of carboxylic acids or halides of the sulfonic acids of General formula VII

R3-X

or VIII

(R3)2O,

where R3has the above value,

in inert solvents, without additives or in the presence of an acid acceptor, in the compounds of General formula I.

4. Pharmaceutical composition having anti-arrhythmic action, including the active ingredient, inert pharmaceutical carriers and excipients, characterized in that as the active ingredient it contains at least one compound of General formula I on p. 1 in quantities of 0.01 to 25 mg/kg

5. The composition according to p. 4 the p. 2.

 

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< / BR>
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