N-2-(1 - r1-5-r2-6-r3- benzimidazolyl)succinamide acid exhibiting neurotic, antihypoxic and antiarrhythmic activity


(57) Abstract:

Usage: as a drug possessing neuroleptic, antihypoxic and antiarrhythmic activity. The inventive product of the General formula where (a) R1=CH3; R2=R3=Br (b) R1= H-C4H9; R2=R3=H (a) so pl. 142-143°C BF C15H19N3O3yield 70% b/ T. pl. 309 310°C, CF C12H11N3O3exit 65% Reagent 1: 2-amino - 1-R1-5-R2-6-R3-benzimidazole Reagent 2: succinic anhydride. Environment: dry dioxane. 6 table.

The invention relates to the synthesis of new biologically active chemical compounds, specifically to N-2-(I-R1-5-R2-6-R3-benzimidazolyl)-Succinimidyl acids of General formula I

where (a) R1=n-C4H9, R2=R3=H;

b) R1= CH3, R2= R3=Br, which have neuroleptic, antihypoxic and antiarrhythmic activity, and can find application in medicine.

Analogues for action are chlorpromazine, sodium oxybutyrate, procainamide drugs, widely used in medical practice.

The aim of the invention is the creation of more effective and minipreparation.

This goal is achieved by a new chemical structure of N-2-(1-R1-5-R2-6-R3-benzimidazolyl)-succinamide acids of the formula I obtained by the reaction of 2-amino-1-R1-5-R2-6-R3-benzimidazole with succinic anhydride in an environment of dry dioxane scheme


The yield of target products was 65-70% of the Compounds Ia,b colorless crystalline substance, soluble in DMF, DMSO, insoluble in acetone and water.

The structure of the synthesized compounds are confirmed by the data of elemental analysis and IR spectroscopy, and individuality was monitored by thin layer chromatography (see tab.1).

P R I m m e R. N-2-(1-butylbenzothiazole)-succineidae acid Ia (see tab.1). To a solution of 1.89 g (0.01 mol) 2-amino-1-butylbenzothiazole in 100 ml of dry dioxane was added a solution of 1.2 g (0.012 mol) of succinic anhydride in dioxane. The reaction mixture is boiled for 2 hours, the excess solvent drove in a vacuum. The precipitation was filtered, washed with water and dried. Yield 2.0 g (70%).

Similarly, the received connection 1B.

Acute toxicity of the compounds under study and comparative drugs were determined in experiments on white mice mA>0compounds 1A and 1B is 380 and 567 mg/kg, respectively.

We studied the effect of compounds 1A,b and chlorpromazine on the latent period Atamanova sleep (see tab.2) and the duration of eleminal-sodium sleep (see tab.3).

Studies have shown that the effect of chlorpromazine on the latent period of sleep at the doses of 10 mg/kg (1/10 LD50) to 0.7 mg/kg (srednestatisticheskaya dose) remained virtually unchanged (1672,6 and 165 of 4.6). The same can be said about the influence of compounds 1A and 1B in doses equal to 1/10 LD50and equimolecular 0.7 mg/kg of chlorpromazine (differences not statistically reliable, see table.2. Therefore, further studies on the claimed compounds in dose, equimolecular 0.7 mg/kg of chlorpromazine.

The influence of compounds on the duration of the latent period eleminal-sodium dream was conducted by the method of [2] in Wistar rats. The investigated compounds were administered at a dose equimolecular 0.7 mg/kg of chlorpromazine, eleminal-sodium at a dose of 40 mg/kg comparison Drug chlorpromazine dose of 0.7 mg/kg On the effect to be judged by the decrease in the latent period before falling asleep.

From table. 2 shows that compounds 1A and 1B in their effects similar to chlorpromazine (180 5, 1901,7 and 1654,6 s, respectively). While the acute 1A and 1B on the duration of eleminal-sodium sleep was studied by the method of [3] Wistar rats (see table.3).

Rats of the first and second groups were injected compounds 1A and 1B, respectively, at doses equimolecular 0.7 mg/kg of chlorpromazine, and after 30 min eleminal-sodium at a dose of 30 mg/kg to Rats of the third group was administered chlorpromazine dose of 0.7 mg/kg and 30 min eleminal-sodium (30 mg/kg). A control group of rats received only eleminal-sodium at a dose of 30 mg/kg On the duration of eleminal-sodium sleep judged on the time during which the animals were housed in an upright position.

The experiments showed that compound Ia increases the duration of sleep compared to the control 2.4 times, and the connection 1B 2.6 times (chlorpromazine 4.7 times). However, the toxicity of these compounds 3.8 and 5.7 times, respectively, lower than that of chlorpromazine.

Adjunct effect of the studied compounds were also assessed by determining the threshold of excitability of the motor centers of the forebrain. frogs. In the acute experience on neobuzdannoe the frog exposed front lobe of the brain, and caused irritation with pacemaker WES-1 bipolar rectangular current pulses, with a duration of 0.5 MS and a repetition rate of 50 pulses per second. Electric irritation of the motor centers of the anterior lobe of the brain, caused by the movement of tunjur brain motor reaction, was estimated as the threshold of irritation [4]

In the experience were compared average values of thresholds of excitability in the initial state and after 15 min during the application of a 2% suspension of the studied compounds. As the comparison drug was used chlorpromazine [5]

The results of the experiments are presented in table. 4. From the data table. 4 shows that the introduction of compounds 1A leads to an increase of the threshold sensitivity of 60% and a connection 1B 35% comparator Drug chlorpromazine significant increase in the threshold of irritation during the application does not.

Defined values of excitability in the initial state and after 30 min after the introduction of the investigated substances in the lymph bag frog (see tab. 4). Compounds 1A and 1B were injected at a dose of 1/10 LD50, chlorpromazine 0.7 mg/kg of Compounds 1A and 1B increase the excitability of 31% and 37%, respectively, and chlorpromazine 18%

In the control groups of animals either during application or during the introduction of saline into the lymphatic bag authentic change of excitability were observed.

Thus, compounds 1A and 1B have a marked dampening effect on the excitability of the motor centers of the forebrain. frogs.

Most compounds is the ability to increase the body's resistance to hypoxia, and also have antiarrhythmic action, affecting the nervous regulation of heart rate [6,7]

So was also studied antihypoxic and antiarrhythmic activity of the claimed N-2-(1-R1-5-R2-6-R3-benzimidazolyl)-succinamide acids. Antihypoxic activity of the studied compounds and the comparison drug sodium oxybutyrate studied in models of normobaric and hypobaric hypoxia [6] at a dose of 1/10 LD50. Normobaric hypoxia was produced by placing the animals in thermocamera volume of 500 ml, with standard values of temperature (18-22aboutC). In the experiments recorded the lifetime of the animal. In thermocamera simultaneously placed the test and control animals. Hypobaric hypoxia was produced by the rarefaction of the atmosphere in the chamber. The partial pressure of oxygen was 37.5 mm RT.article Speed "recovery" of animals to a height of 1500 m was equal to 30 m/s In the chamber at the same time put the test and control animals. The exposure time of animals in the chamber 30 min. the results of the experiments are presented in table.5.

Compounds 1A and 1B on the model normobaric hypoxia showed approximately equal activity. They increased the duration of x hypobaric hypoxia with the introduction of compounds 1A and 1B, the animals were killed within 30 min (the time of exposure in the chamber, i.e., their life expectancy has increased more than 5 times. Sodium oxybutyrate in these conditions increases the life expectancy of animals 3 times.

Antiarrhythmic activity of the claimed compounds was studied on the model chloralkali adults in outbred rats. Arrhythmia was modeled according to the method of [8] simultaneous introduction of a 10% aqueous solution Cl2(200 mg/kg) into the femoral vein. The analyte and the reference product was administered at a dose of 1/10 LD50. The data obtained are given in table.6.

Studies have shown that the introduction of compounds 1A leads to increased survival rate of animals in 2.5 times, compared with procainamide. This connection is stronger procainamide hydrochloride and antifibrillatory activity. Compound 1B increases the survival rate of animals at the level of the comparison drug.

Thus, the claimed compounds 1A,b in neuroleptic effect on indicators of the latent period eleminal-sodium sleep equal to chlorpromazine, but the effect on the magnitude of the threshold of excitability of the forebrain. frogs superior to chlorpromazine 50 and 25%, respectively. While acute toxicity of the inventive compounds 3.8 and 5.7 times, respectively, lower than VA the lives of animals in thermocamera 2.0 and 2.1 times, respectively (sodium oxybutyrate 1.5 times). In the conditions of hypobaric hypoxia their life expectancy has increased more than 5 times (sodium oxybutyrate 3 times).

On antiarrhythmic action (indicator surviving animals) compound 1B is procainamide, 1A and the connection exceeds 2.5 times.

N-2-(1-R1-5-R2-6-R3-Benzimidazolyl)succinamide acid of General formula

< / BR>
where (a) R1CH3, R2R3Br;

b) R1H C4H9, R2R3hydrogen

exhibiting neurotic, antihypoxic and antiarrhythmic activity.


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(1) where R1the atom of hydrogen, fluorine, chlorine or bromine, alkyl-, aralkyl-, aryl-, heteroaryl-, R3O-, (R3)2N-, R4CO - NR3-, alkylsulfonyl - NR3-, arylsulfonyl - NR3-, R3S-, R3SO, R3S2O-, or R5group, and R3is a hydrogen atom, an alkyl group containing from 1 to 6 carbon atoms, aryl, heteroaryl, kalkilya, carboxialkilnuyu or alkoxycarbonylmethyl group;

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RR6(I) in which groups are represented as follows: R1, R2, R3independently represent a hydrogen atom, hydroxy group, lower alkyl group, which optionally can be substituted by halogen atom, lower alkoxy group, a lower alkylthio group, aralkylated group, aryloxy group, lower alkanoyloxy group, carboxy group, lower alkoxycarbonyl group or nitro group;

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The invention relates to compounds of the formula I

(I) or pharmaceutically acceptable salt accession acids him or stereoisomeric form of the compound, where

-A1= AND2- A3= AND4- bivalent radical having the formula

-CH=CH-CH=CH- (a-1)

-N=CH-CH=CH- (a-2)

-CH=CH-CH=N (a-5) or

-N=CH-N=CH- (and-6),

n=1 or 2

IN - NR4or CH2< / BR>
R4is hydrogen or C1-C6alkyl

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-Alk - R5(b-1),

-Alk - Y - R6(b - 2),

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-CH2- SNON - CH2- O - R8(b-4), where R5is cyano, phenyl optionally substituted C1-C6alkyloxy; pyridinyl; 4,5-dihydro-5-oxo-1-N-tetrazolyl; 2-oxo-3-oxazolidinyl; 2,3-dihydro-2-oxo-1-N-benzimidazolyl; or bicycling radical of formula (C-4-a)

Gwhere G2- CH=CH-CH=CH-, -S-(CH2)3,- -S-(CH2)/2-, -S-CH=CH - or-CH=C(CH3)-O-;

R6- C1-C6-alkyl, pyridinyl optionally substituted by nitro; pyrimidinyl; feast
R7- C1-C6-alkyl; halophenol; 1-methyl-1H-pyrrolyl; furanyl, thienyl, or aminopyrazine;

R8- halophenol;

Y is O or NH;

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each Аlk independently - C1-C6alcander

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(I)< / BR>
(II),whereR is the residue of carboxylic acids, which are used as intermediates in obtaining antibiotics cephalosporin and penicillin ranks as the number of individual substances and mixtures

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