Derivatives of benzimidazole with antihistaminic activity

 

(57) Abstract:

Usage: in medicine, in particular as a compound with antihistaminic activity. The inventive product is a derivative of benzimidazole f-ly I, where R1and R2- equal or different, represent H, halogen, lower alkyl, hydroxy-, alkoxy-, carbalkoxy not or substituted aryl; n = 0-1; m = 2-4; X, Y, Z, and W are equal or different and also forming a part of another aromatic or nonaromatic cycle are nitrogen or carbon, associated with halogen, or such radicals as alkyl, aryl, carboxylic, carbalkoxy, sulfo or alkylsulfonate. table 4.

The invention relates to new derivatives of benzimidazole, method of production thereof and their use as medicines.

Compounds that are the subject of the present invention meet the General formula:

RNN(CH2)N where R1and R2the same or different, represent a hydrogen atom, a halogen, a lower alkyl radical, a hydroxy radical, an alkoxy radical, a radical of carbalkoxy,the radical aryl or substituted aryl radical, n can have the values 0 or 1, m can have values 2-4, X, Y, Z and W are identical or different and which form part of each is hydrogen, with halogen or with another radical-alkyl, aryl, carboxylic, carboxyl, hydroxyl, alkylperoxy, sulfo and alkylsulfate.

Known derivatives of benzimidazole with various biological activities, such as analgesic and anti-inflammatory activity (Japan Kokai 75, 126, 682), gastric antisecretory activity (European patent NN 246126 and 5129); anti-histamine activity (J, Jilek et al., Coll ect. Czech. Chem. Commun., 1988, 53, 870-83; U.S. patent N 4200641; Drugs of the Future, the UE; 10-1. 1982; R. Iemura et al., Y. Med. Chem. , 1986, 29, 1178-1183; R. Iemura et al., J. Heteroxycyclic. Chem., 1987, 24, 31-37). Compounds that are the subject of the present invention is new derivatives of benzimidazole, and specifically 1-(2-ethoxyethyl)-2-(alkylpiperazine)of gasoline - midazol. These new derivatives have a very good anti-histamine activity and they do not have side effects on the Central nervous system.

New derivatives of General formula 1 can be obtained according to the invention, one of the following methods:

Method A. By reaction of compounds of General formula IIa:

RNN(CH2)m-A

or IIb:

RN where R1, R2n and m have the above meanings and a represents a halogen or a leaving group derived values.

The reaction is carried out in the presence of a solvent, such as dimethylsulfoxide, dimethylformamide, alcohols, hydrocarbons, aromatic or non-aromatic, ethers, such as dioxane or diphenyl ether, or mixtures of these solvents. This reaction mainly occurs in the presence of such grounds, as hydroxides, carbonates or bicarbonates of alkali metals, or mixtures of these bases. You can also use the hydrides of alkali metals. The most suitable temperature between ambient temperature and the boiling temperature of the solvent, and the reaction time is 1-24 hours

Method C. By the reaction of compounds of General formula IIa, in which a represents the radical - NH2with a 2.5-dimethoxytetrahydrofuran.

The reaction is carried out in the presence of a solvent, for example, acetic acid, water, alcohols, ketones or mixtures of these solvents. The most suitable temperatures range between ambient temperature and the boiling point of the solvent, and the reaction time is from several minutes to 24 hours

Method C. By the reaction of compounds of General formula IV:

RNNH where R1, R2and n have the above meanings, with a compound of General formula V

B-(CH2)N vasilaki or mesilate.

The reaction is carried out in the presence of a solvent, such as dimethylsulfoxide, dimethylformamide, alcohols, hydrocarbons, aromatic or non-aromatic, ethers, such as dioxane or diphenyl ether, or mixtures of these solvents. This reaction mainly occurs in the presence of such grounds, as hydroxides, carbonates or bicarbonates of alkali metals, or mixtures of these bases. The most suitable temperatures range between ambient temperature and the boiling temperature of the solvent, and the reaction time is 1-24 hours

In the following examples shows how to obtain the new derivatives according to the invention.

Method A.

P R I m e R 1. Obtain 1-(2-ethoxyethyl)-2-{4-[4-(4-bromopyrazole-1-yl) butyl] piperazine-1-yl-methyl} benzimidazole.

a) Bromide 1-(2-ethoxyethyl)-2-(8-methylase-5-isoniazide)benzimidazole.

Boiled for 16 h, the mixture of 1.5 g (to 5.21 mmol) 1-(2-ethoxyethyl)-2-(1-piperazinil)benzimidazole, of 1.41 g (6.5 mmol) 1-4-dibromobutane and 0.72 g (5.2 mmol) of potassium carbonate in 50 ml of chloroform. Cooled, filtered and evaporated. Dissolve the residue in ethyl ether and obtain 2.1 g of the bromide 1-(2-ethoxyethyl)-2-(8-methylase-5 - Sonisphere Dean)benzimidazole, gignosko is (t, 3H); to 2.25 (m, 4H); 3.25 to to 4.15 (m,N); of 4.45 (t, 2H); 7,27 (m, 3H); 7,60 (m, 1H).

b) 1-(2-Ethoxyethyl)-2-{ 4-[4-(4-bromopyrazole-1-yl) butyl] piperazine-1-yl-methyl} benzimidazole.

Heated to boiling for 12 hours a mixture of 2.3 g (5,44 mmol) of bromide 1-(2-ethoxyethyl)-2-(8-methylase-5-Sonisphere Dean/benzimidazole, 0,92 g (6,28 mmol) 4-bromo-1-H-pyrazole, to 1.38 g (0.01 mol) of potassium carbonate and 30 ml of dimethylformamide. Cooled, filtered and the filtrate is evaporated to dryness. The residue is treated with chloroform and washed with water. The organic phase is dried with Na2SO4, filtered and evaporated. The resulting oil is purified on a chromatographic column of silica (eluate: chloroform-methanol 95:5).

So, get 0,78 g of compound in liquid form.

Spectroscopic data for identification are given in table. 1 and 2.

P R I m m e R 2. Obtain 1-(2-ethoxyethyl)-2-{4-[4-(4-bromopyrazole-1-yl-butyl] piperazinil} benzimidazole.

a) Bromide 1-(2-ethoxyethyl)-2-(8-Aza-5-Sonisphere Dean)benzimidazole.

Receive the same manner as in example 1A.

1H-NMR (CDCl3): a 1.08 (t, 3H); is 2.37 (m, 4H); 3.42 points (q, 2H); 3,7-to 4.15 (m, 14H); 4,32 (t, 2H); 7,27 (m, 3H); 7,60 (m, 1H).

b) 1-(2-Ethoxyethyl)-2-{ 4-[4-(4-bromopyrazole-1-yl) butyl] piperazinil} Ben who get in ethanol, and its melting point is 137-139aboutC. Spectroscopic data for the identification are given in table. 1 and 2.

P R I m e R 3. Obtain 1-(2-ethoxyethyl)-2-{4-[4-(1-the imidazole) butyl] piperazine-1-yl-methyl} benzimidazole.

Get as shown in the examples 1A and 1B. Spectroscopic data for identification are given in table. 1 and 2.

P R I m e R 4. Obtain 1-(2-ethoxyethyl)-2-{4-[4-(1,2,4-triazole-1-yl) butyl] piperazine-1-yl-methyl} benzimidazole.

Get as in examples 1A and 1B.

Spectroscopic data for identification are given in table. 1 and 2.

P R I m e R 5. Obtain 1-(2-ethoxyethyl)-2-{4-[4-(4-sulfaphenazole-1-yl) butyl] piperazine-1-yl-methyl} benzimidazole.

Get as shown in the examples 1A and 1B.

Spectroscopic data for identification are given in table. 1 and 2.

P R I m e R 6. Obtain 1-(2-ethoxyethyl)-2-{4-[4-(4-carboxybenzoyl-1-yl/butyl] piperazine-1-yl-methyl} benzimidazole.

According to the method according to examples 1A and 1B receive the crude 1-(2-ethoxyethyl)-2-{ 4-[4-(4-ethoxycarbonyl-pyrazole-1-yl) butyl] piperazine-1-yl-methyl} benzimidazole, which is purified on a chromatographic column of silica (eluant: holdem is 0-4,3 (m, 4H); 4,50 (t, 2H); 7,28 (m, 3H); to 7.75 (m, 1H); 7,8 (s, 2H).

IR (film): 1715, 1560, 1470, 1225, 1120, 1040, 750 cm-1.

Salt with maleic acid is obtained in ethanol, and its melting point is 114-117aboutC.

Prior ester hydrolized by treatment of a solution in ethanol for 3 h at ambient temperature, 10% sodium hydroxide. Evaporate the alcohol and water solution is neutralized with acetic acid. Is evaporated to dryness, and the acid is extracted from the precipitate by evaporation of dichloromethane.

Hence, receive the appropriate acid, spectroscopic data, to identify, bring to the table. 1 and 2.

P R I m e R 7. Obtain 1-(2-ethoxyethyl)-2-{4-[4-(1-pyrazolyl)butyl] piperazine-1-yl-methyl} benzimidazole.

Get as shown in the examples 1A and 1B.

Salt with maleic acid is obtained in ethanol melting point wing 112-116aboutC. Spectroscopic data for the identification are given in table. 1 and 2.

P R I m e R 9. Obtain 1-(2-ethoxyethyl)-2-{4-[4-(4-carboxybenzoyl-1-yl/butyl] piperazine-1-yl} benzimidazole.

According to the method shown in examples 2A and 2B receive the crude 1-(2-ethoxyethyl)-2-{ 4-[4-(4-atrocitie silicon (eluant: chloroform-methanol 95:5).

1H-NMR (CDCl3): 1,1 (t, 3H); 1,3 (t, 3H), 1.8 m (m, 4H); 2,15-2, 7 (m, 6N) at 3.25 (m, 6N), and 3.7 (t, 2H), 3,8-4,3 (m, 6N), to 7.2 (m, 3H); 7,5 (m, 1H); 7,8 (s, 2H). IR (KBR): 2950, 1715, 1220, 1125, 760 cm-1.

Prior ester hydrolized by treatment of a solution in ethanol for 15 h at ambient temperature, 10% sodium hydroxide. Evaporate the alcohol and water solution to neutralize hydrochloric acid. Is evaporated to dryness, and the acid is extracted from the precipitate by evaporation of chloroform.

Thus, receive the corresponding acid, which is diluted with ethyl ether. The compound crystallized in the solvent with a melting point 145-150aboutC.

Spectroscopic identification data in the table. 1 and 2.

P R I m e R 10. Obtain 1-(2-ethoxyethyl)-2-{4-[4-(4,5-dichloroimidazole-1-yl) butyl] piperazine-1-yl-methyl} benzimidazole.

Get as shown in the examples 1A and 1B.

Salt with fumaric acid get in ethanol melting point 123-130aboutC. Spectroscopic data for the identification of lead in the table. 1 and 2.

Method C.

P R I m e R 8. Obtain 1-(2-ethoxyethyl)-2-{4-[4-(1-pyrrolyl) butyl] piperazine-1-yl-methyl} benzimidazole.

a) 1-(2-Hetq) 1-(2-ethoxyethyl)-2-(1-methylpiperazine)benzimidazole, of 6.26 g (22 mmol) of N-(4-bromobutyl)phthalimide, 4,55 g (33 mmol) of potassium carbonate and to 4.62 g (30 mmol) of sodium iodide in 100 ml of methyl ethyl ketone. Cooled, filtered and the filtrate is evaporated to dryness. Treat the residue with chloroform and water, the organic phase is dried with Na2SO4, filtered and evaporated in vacuum. The resulting oil is purified on a chromatographic column of silica (eluant : chloroformmethanol 95: 5). Thus, the gain of 8.47 g of 1-(2-ethoxyethyl)-2-{4-(4-N-phthalimido-butyl)piperazine-1-yl-methyl} benzimidazole.

1H-NMR (CDCl3): 1,1 (t, 3H); 2.6 (m, 4H); of 2.45 (m, 10H) to 3.3 (q, 2H); 3.5 to 3.8 (m, 6N), and 4.4 (t, 2H), 7,15 (m, 4H); at 7.55 (m, 4H).

Heated at boiling for 2 h, the solution 8,46 g (17.3 mmol) of the previously obtained compound and 1.73 g (34.6 mmol) of hydrazine hydrate in 150 ml of ethanol. Cooled, filtered, washed with ethanol and the filtrate is evaporated to dryness in a vacuum. Treat the residue with chloroform, and washed with water, dried, evaporated and obtain 4.35 g of 1-(2-ethoxyethyl)-2-ethoxyethyl)-2-{ 4-(4-aminobutyl)piperazine-1-yl-methyl} benzimidazole, which is used without other purification.

1H-NMR (CDCl3): 1,1 (t, 3H), of 1.45 (m, 4H), of 1.75 (s, 2H); 2.05 is is 2.75 (m, N), the 3.35 (q, 2H), 3,6-3,9 (m, 4H), of 4.45 (t, 2H); 7,20 (m, 3H), 7,6 (m, 1H).

b) 1-(2-Ethoxyethyl)-2-{ 4-[4-(1-prolinol) 1-(2-ethoxyethyl)-2-{ 4-(4-aminobutyl)-piperazine-1-yl - methyl} benzimidazole and 0,735 g (to 5.57 mmol) of 2,5-dimethoxytetrahydrofuran in 20 ml of acetic acid. Cooled, poured into ice water, neutralized with NaHCO3and extracted with chloroform. Dried with Na2SO4and evaporated to dryness in a vacuum. Thus, the gain of 2.75 g of the crude compound, which was purified on a chromatographic column of silica (eluant: chloroform - methanol 94: 6).

Salt with fumaric acid get in ethyl ethanolamine with a melting point 138-142aboutC.

Spectroscopic data for the identification of lead in the table. 1 and 2.

Method C.

P R I m e R 6. Obtain 1-(2-ethoxyethyl)-2-{4-[4-(4-carboxybenzoyl-1-yl) butyl] piperazine-1-yl-methyl} benzimidazole.

Boiled for 4 hours a mixture of 5 g (17,36 mmol) 1-(2-ethoxyethyl)-2-(1-methylpiperazine)benzimidazole, 4.77 g (17,36 mmol) 1-(4-bromobutyl)-4-pyrazolecarboxylate-La, 3,60 (26 mmol) of potassium carbonate and to 3.52 g (23.5 mmol) of sodium iodide in 100 ml of methyl ethyl ketone. Cooled, filtered and evaporated to dryness.

Treat the residue with chloroform and water, the organic phase is dried with Na2SO4, filtered and evaporated in vacuum. The crude compound purified on a chromatographic column of silica (eluant: chloroform-methanol 95: 5) and, thus, receive 4,85 g of 1-(troscopically data connections are the same as already shown in example 6 according to the method of A.

This ester hydrolyzing similar to the method shown in example 6 method and get the acid with the same spectroscopic data as the data are given in table. 1 and 2.

P R I m e R 8. Obtain 1-(2-ethoxyethyl)-2-{4-[4-(1-pyrrolyl/butyl] piperazine-1-yl-methyl} benzimidazole.

Get as shown in the previous example, and get a connection, salt with fumaric acid has a melting point 137-142aboutC.

Spectroscopic data for identification are the same as presented in table. 1 and 2.

Pharmacological activity.

The products that are the subject of the present invention are potent anti-histamine compounds, which differ in that they are free from the depressing effect in contrast to most known anti-histamine compounds.

Anti-histamine activity in vivo.

Anti-histamine activity was investigated by determining the protection from death caused by product 48/80 in rats. This study was conducted according to the technology described in C. J. E. Niemegeers et cols. (Arch. int. Pharmacodyn. ,m After 60 minutes of entering the compound 48/80 (0.5 mg/kg, i.v.). Protective activity manifests itself as the survival of rats within 4 h after injection i.v. compound 48/80.

Examine the activity of products with multiple doses to determine the dose capable of protecting 50% of animals (DE-50).

Below is a anti-histamine activity of some products. This activity compared with the activity of diphenhydramine, which is the control antihistaminics connection. Most of the products are more active than diphenhydramine, given that their DE-50 is much lower.

Anti-histamine activity in vivo:

Protection from death induced by compound 48/80 Example DE-50 (mg/kg, i, p)

1 0,09

2 2,7

3 0,13

4 being 0.036

5 2,6

6 0,064

7 0.02

8 0.02

9 0,84

10 0,66 Diphenhydramine 5,4

Calming effect: 1/ Test of Irvine.

To study the absence of the soothing effect of the products they are administered to rats vnutrepenialnymi and by observing the behavior of animals in accordance with the standards described in the test of Irvine (Science, 136, 123-128 (1962)).

s. : Passivity, calm, prostration. Quantitative score from 0 to 3 . It is conducted through 1,2 and 3 h P3. Evaluated after 1, 2 and 3 h after treatment.

In table. 3 the results of study of the sedative effect of some products that are the subject of the present invention. This activity compared with the activity of diphenhydramine, which is the control antihistaminics connection. The products that are the subject of the present invention, show a very weak calming effect in contrast diphenhydramine, which turns out to be toxic at the dose of 80 mg/kg, i,R. due to the depressive effects of the SNC.

Calming effect: 2. Stimulation time of sleep induced by pentobarbital.

The study of stimulus-time sleep due to the introduction of pentobarbital performed according to the method described in Z. E. Allen et cols. (Arz. Forsch. 24, (6), 1974). Researched products administered orally. An hour later enter pentobarbital sodium (35 mg/kg) and determine the delay time Wake-up animals. Compare the night with a group of control animals treated only with pentobarbital sodium.

To complement studies that prove the absence of the depressing effect of the products that are the subject of the present invention, in this test compared aktualnym antihistamines connection, by diphenhydramine. In table. 4 the results of this test using the compounds according to example 7 and diphenhydramine. Obviously, diphenhydramine potentialities largely bedtime dose of 20 mg/kg, while the compound from example 7 is not potentialities sleep time induced by pentobarbital, even at the highest tested dose of 320 mg/kg

Calming effect: 2) Stimulation time of sleep induced by pentobarbital.

Below, as an example individual herbal form of derivatives, which are the subject of the present invention.

Tablets.

The formula for tablet

Connection example 7, mg 10.00 Lactose, mg 54,00 Corn starch, mg 26,60

Microcrystalline cellulose, mg 18,00 Polyvinylpyrrolidone, mg 6,00 Crosscarmellose sodium, mg 3,60

Colloidal flint - Wai dioxide, mg to 0.60 magnesium Stearate, mg 1,20

________< / BR>
120,00

Derivatives of benzimidazole of General formula

R(CH2)nNN(CH2N

where R1and R2- same or different, hydrogen, halogen, lower alkyl, hydroxy-, alkoxy-, carbalkoxy, aryl or substituted aryl;

n=0-1;

m=2-4;

X, Y, Z and W - dynamogeny with hydrogen, halogen or with such radicals as alkyl, aryl, carboxylic, carbalkoxy, hydroxyl, alkylperoxyl or alkylsulfonate,

with antihistaminic activity.

 

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