Derivatives of benzimidazole, antihistamine pharmaceutical composition and method of treatment of allergic diseases

 

(57) Abstract:

The invention relates to new derivatives of benzimidazole of formula 1, where R1represents hydrogen or hydrocarbon group with a short chain, R2- CH2HE, COOH, R34,4-dimethyl-2-oxazoline. This invention relates to compounds having a strong selective H1-antihistamine activity which has no activity against Central nervous system, and therefore can be used for treatment of allergic diseases and as an active ingredient antihistamine farbkomposition. 3 S. and 6 C.p. f-crystals.

The purpose of the invention

The present invention relates to new derivatives of benzimidazole with H1-antihistamine activity, 't have cardiotoxic effects.

Background of the invention

The closest to the compounds of the present invention are compounds described in the patent Spain 9201512, which describes a series of benzimidazole derivatives of piperidine with antihistaminic and antiallergic activity of the General formula:

< / BR>
The main structural difference between the compounds of the present invention and soedinenii group. In addition, it was found important pharmacophoric nature of these oxygen-containing functional groups, which consists essentially in selectivity effects and provides a pharmacological profile different from the profile of other well-known antihistamine substances. Compounds described in this invention, are almost exclusively H1-antihistamines pharmacological activity and are therefore free from the influence of other pharmacological receptors even at doses much higher than the pharmaceutical. Due to the selectivity of their action, they are valuable tools in the treatment of allergic conditions of the type, in particular, giving unlimited use by persons receiving simultaneously any other treatment, and in the case of patients with pathological disorders cardiac circulation.

Description of the invention

Since it is well known that histamine plays a very important role in diseases of the allergic type, such as allergic rhinitis, conjunctivitis, urticaria and asthma, antihistamine compounds acting at the level of H1-histamine receptor, are useful for the treatment of such SOS is AK sedation and dry mouth, resulting from their actions on the Central nervous system and cholinergic receptors.

The search for molecules that do not cross the blood-brain barrier, causing the replacement of early antihistamines other antihistamines second generation, which overcame the adverse effects associated with their effect on the Central nervous system. This new generation of antihistamines, among which deserve attention due to their wide use around the world, terfenadine and astemizole, in recent years show a negative aspect in the form of dangerous cardiovascular effects that apply to QT-region and ventricular fibrillation, which demanded that their use was excluded in cases in which the patient tends to suffer from such disorders or when treated with substances that can interfere with its metabolism.

Attempts to obtain safe and effective H1-antihistamines have multiplied in recent years, and the present study results in several recent patent applications, in which the claimed pharmaceutical composition for the treatment of allergic diseases U.S. patent number 924156 (3/08/092) and application for international patent number 95/00480 (05/01/095).

The present invention relates to a group of new compounds of benzimidazole structure, with a strong selective1-antihistamine activity which has no activity against Central nervous system and cardiovascular system.

Compounds that are the subject of the present invention are compounds having the following General formula:

(1)

in which R1represents hydrogen or hydrocarbon group with a short chain, such as methyl, ethyl, isopropyl, cyclopropyl or vinyl, and R2represents a group selected from CH2HE, COOH, COOR34,4-dimethyl-2-oxazoline, and R3is an alkyl group with a short chain, as defined above, and their acid additive salts with pharmacologically acceptable acids or bases.

Compounds I in which R1is an alkyl group with a short chain and R2is 4,4-dimethyl-2-oxazolidone group, can be conveniently obtained by reaction of N-alkylation of 2-(4-piperidinyl)-lH-benzimidazole with an alkylating agent of the formula III, where X is a good leaving group in nucleophilic substitution, such as C1, Br, I, R2CH2OR1where X has the values given above, and R1is a hydrocarbon group with a short circuit, such as Me, Et, ISO-RG, cyclopropyl, vinyl, etc. in the presence of a hydride or carbonate of an alkali metal.

< / BR>
Compounds I in which R1is an alkyl group with a short chain and R2is a carboxyl group-friendly manner can be obtained by hydrolysis of benzimidazole Ia inorganic acid, such as model HC1 or H2SO4.

< / BR>
Compounds I in which R1is an alkyl group with a short chain and R2is a group R3in which R3is an alkyl group with a short circuit, can be obtained by acid hydrolysis of benzimidazole Ia in the presence of an alcoholic solvent R3HE under appropriate conditions for the transesterification.

< / BR>
Compounds I in which R1is an alkyl group with a short chain and R2is a group CH2IT can be obtained by recovery of benzimidazole Ib or IC suitable Vosstania the camping hydrogen and R2is 4,4-dimethyl-2-oxazolidone group, can be obtained by alkylation of benzimidazole IV ethylparathion in the presence of a hydride or carbonate of an alkali metal with the receipt of ester V, which is then restored using a reducing agent such as aluminum hydride and lithium.

< / BR>
Compound I, in which R1is hydrogen and R2is a COOH group, conveniently obtained by hydrolysis of an inorganic acid, such as Hcl or H2S04that connection is used.

< / BR>
Received new benzimidazole I can be converted into pharmaceutically acceptable salts by treatment with suitable acids or bases.

The compounds of formula I have useful pharmacological properties. In particular, they are potent H1-antihistamines. Their activity is clearly demonstrated in vitro by blocking induced by histamine contractions in the isolated ileum of the Guinea pig (Magnus, Pflugers, Arch. Ges. Physiol., 102, 123 (1904); Arunlakshana, 0. and Schild, H. O., Br. J. Pharmacol., 14, 48-58 (1959) and in vivo no ability to inhibit the increase induced by histamine permeability of skin capillaries in rats (Lefebvre, P., Salmon, J., Lec, compound Ib (R1=ethyl) was a potent mixed antagonist of H1-vitaminnogo receptor in the ileum of the Guinea pig, and the calculated value of RA2=7,98-8,10 and pD2'=6,50. To the same compound inhibits in vivo increase in capillary permeability in rats with value DE50close to 2 mg/kg, when administered orally. At doses of 5 mg/kg when administered orally it supports a significant activity more than 50% for at least 6 hours.

These compounds are highly selective in their pharmacological action and do not show significant antiholinergicescoy activity or activity in relation to the Central nervous or cardiovascular systems. Thus, compound Ib (R1=Et) is not able to anlagenservice largely induced by acetylcholine contractions of the ileum Guinea pigs at concentrations of 0.1 M and does not alter the spontaneous locomotor activity of rats at the dose of 100 mg/kg orally; in addition, the same compound administered intravenously at a dose of 20 mg/kg, does not cause morphological disorders in ECG and does not increase QTcthe interval in rats.

In view of their useful pharmacological antissa in various pharmaceutical forms for further introduction oral, topically, by injection, or rectally. Preparations for oral administration are obtained by thorough mixing, an effective antihistaminic amount of one of the products described in this invention, excipients such as lactose, cellulose, talc and similar for tablets or capsules, or water, glycols, alcohols, oils and the like for syrups, solutions and suspensions. Local injection may be in the form of creams, ointments, gels, solutions, patches and for insertion through the skin with the use of agents, such as petrolatum, polyethylene glycols and similar media. In preparations for injection filler may be at least in the most part, sterilized water, although you can add other fillers, such as saline solutions, glucose solutions and similar or mixtures thereof, to increase the solubility.

Examples, discussed below, illustrate the present invention without limiting its scope.

Example 1

Obtain 1-(2-ethoxyethyl)-2-[1-(2-(4-(1-(4,4-dimethyl-2-oxazoline-2-yl)-1-(methylethyl)phenyl)ethyl)piperidine-4-yl]-1H-benzimidazole (Ia, R1=Et)

3.57 g of sodium carbonate are added to a suspension of 14 g is dazole in 60 ml of DMF, and the resulting suspension is heated at 80oC for 14 hours. DMF and concentrate the reaction was poured into water/ice, and then crystallized solid product which was filtered, washed with water and dried at 50oWith obtaining 10 g 2-[1-(2-(4-(1-(4,4-dimethyl-2-oxazoline-2-yl)-1-methylethyl)phenyl)ethyl)piperidine-4-yl] -1H-benzimidazole. The obtained solid product is dissolved in 25 ml of DMF and to it add 1.2 g of sodium hydride 60% oil suspension. The resulting suspension is stirred at room temperature for two hours and type of 2.44 g of 2-chloroethylamino ether. The reaction mass is heated at 80oC for 16 hours, cooled, poured into water/ice, extracted with ether and washed with water and saturated sodium chloride solution. The ether solution is dried over anhydrous sodium sulfate and concentrated to obtain 11.2 g of 1-(2-ethoxyethyl)-2-[1-(2-(4-(1-(4,4-dimethyl-2-oxazoline-2-yl)-1-methylethyl)phenyl) ethyl)piperidine-4-yl] -1H-benzimidazole. So pl. : 98-100oC (ethanol).

NMR1N (D13), : 1,1 (t, 3H); 1,3 (C, 6N), and 1.5 (s, 6N); 1,9 (m, 2H); 2,1 (m, 4H); 2,6 (t, 2H); and 2.8 (t, 2H); 3,0 (m, 1H); 3,1 (d, 2H); 3,4 (s, 2H); 3,7 (t, 2H); 3.9 to (s, 2H); 4,3 (t, 2H); 7,1-7,3 (m, 7H); of 7.7 to 7.8 (m, 1H).

NMR13With (CDCl3), : 14,96; 27,38; 28,15; 31,06; 33,10; 34,53; 40,18; Uchenie 2-[4-(2-(4-(1-(2-ethoxyethyl)benzimidazole-2-yl)-piperidine-1-yl)ethyl)phenyl]-2-methylpropanoic acid (Ib, R1=Et)

6,72 g of 1-(2-ethoxyethyl)-2-[1-(2-(4-(1-(4,4-dimethyl-2-oxazoline-2-yl)-1-methylethyl)phenyl)ethyl)piperidine-4-yl] -1H-benzimidazole (Ia) is dissolved in 170 ml of 3h. HCl and heated under reflux for one hour. The solution is cooled and brought to pH 7 with 50% sodium hydroxide. The solution is extracted with n-butanol, washed with water, dried over anhydrous sodium sulfate and concentrated. To the residue is added methanol (30 ml) and 50% sodium hydroxide solution (40 ml) and heated under reflux for thirty minutes. The methanol is distilled off and water is added to until dissolution is complete. This solution is extracted with ether and the aqueous layer was adjusted to pH 7 with 20% model HC1 and saturated with sodium chloride, after which the precipitated solid product was filtered, washed repeatedly with water and dried in a vacuum drying apparatus at 50oWith obtaining 3.5 g 2-[4-(2-(4-(1-(2-ethoxyethyl)benzimidazole-2-yl)piperidine-1-yl)ethyl)phenyl]-2-methylpropanoic acid.

So pl. 199-201oWITH

NMR1H (DMSO-d6), : 1,0 (t, 3H); 1,4 (C, 6N); and 1.8 (m, 4H); 2,2 (m, 2H); 2,5 (t, 2H); and 2.7 (t, 2H); 3,0 (m, 3H); 3,3 (s, 2H); 3,6 (t, 2H); 4,4 (t, 2H); 7,0-to 7.3 (m, 6N); 7,4-7,6 (m, 2H).

NMR13(DMSO-d6), : 14,90; 26,59; 30,97; 32,22; 33,39; 43,04; 45,50; 53,08; 60,05; 65,70; 68,43; 110,18; 118,40; 121,16; idazole-2-yl)piperidine-1-yl)ethyl)phenyl]-2-methylpropanoate (Ic, R1=ET, R3=ET)

Concentrated sulfuric acid (20 ml) is added over a solution of 10 g of 1-(2-ethoxyethyl)-2-[1-(2-(4-(1-(4,4-dimethyl-2-oxazoline-2-yl-1-methylethyl)phenyl)ethyl)piperidine-4-yl] -lH-benzimidazole in 250 ml of ethanol and the solution heated under reflux for 16 hours. The solution is cooled and add 1 liter of ether. The organic layer is separated and washed with water, 10% sodium bicarbonate solution and again with water. This product is dried over anhydrous sodium sulfate and concentrated to obtain 7 g of oil, which is purified by flash chromatography using a mixture of 95/5 chloroform/ethanol as eluent to obtain 5 g 2-[4-(2-(4-(1-(2-ethoxyethyl)benzimidazole-2-yl)piperidine-1-yl)ethyl)-phenyl]-2-methylpropanoate in the form of butter.

NMR1N (D13), : 1,1 (t, 3H); 1,2 (t, 3H); 1,5 (C, 6N); 2.0 (m, 2H); 2,2 (m, 4H); 2,6 (t, 2H); and 2.8 (t, 2H); 3,0 (m, 1H); 3,2 (m, 2H); 3,4 (s, 2H); 3,7 (t, 2H); to 4.1 (s, 2H); 4,3 (t, 2H); 7,1-7,3 (m, 7H); of 7.6 to 7.7 (m, 1H).

NMR13(D13), : 13,86; 14,80; 26,35; 30,62; 32,73; 33,87; 43,48; 45,91; 53,26; 60,11; 60,49; 66,61; 68,40; 109,02; 119,16; 121,55; 121,75; 125,40; 128,50; 134,56; 138,40; 142,29; 142,51; 158,13 and 176,53.

Example 4

Obtain 1-(2-ethoxyethyl)-2-[1-(2-(4-(1,1-dimethyl-2-hydroxyethyl)phenyl)ethyl)piperidine-4-yl]-1H-benzimidazole (Id, R1=Et)

1G aluminiumhydride lidin-1-yl)ethyl)phenyl] -2-methylpropanoate. The solution is stirred for four hours at room temperature and add a few milliliters of water to remove excess hydride. The solution is filtered and the filtrate washed with a saturated solution of sodium chloride. The filtrate is dried and concentrated. The residue re-dissolved in chloroform and washed with water, dried and concentrated. The residue is purified by flash chromatography, using as eluent a mixture of hexane/ether/Isopropylamine (2/7,5/0,5) to obtain 1.5 g of 1-(2-ethoxyethyl)-2-[1-(2-(4-(1,1-dimethyl-2-hydroxyethyl)phenyl)ethyl)piperidine-4-yl]-lH-benzimidazole.

So pl.: 112-114oWITH

NMR1H (CDCl3), : 1,0 (t, 3H); 1,4 (C, 6N); 1,9-2,1 (m, 2H); to 2.1-2.3 (m, 4H); 2,6 (t, 2H); and 2.8 (t, 2H); 3,0 (m, 1H); 3,2 (d, 2H); 3,4 (s, 2H); 3,6 (s, 2H); 3,7 (t, 2H); 4,3 (t, 2H); and 7.1 to 7.4 (m, 7H); of 7.8 (m, 1H).

NMR13With (CDCl3), : 15,01; 25,34; 31,07; 33,07; 34,53; 39,78; 43,64; 53,72; 60,52; 66,88; 68,62; 73,07; 109,13; 119,44; 121,77; 121,94; 126,22; 128,80; 134,78; 138,39; 142,71; 143,90; 158,45.

Example 5

Obtain 1-(2-hydroxyethyl)-2-[1-(2-(4-(1-(4,4-dimethyl-2-oxazoline-2-yl)-1-methylethyl)phenyl)ethyl)piperidine-4-yl]-1H-benzimidazole (S)

5 g 2-[1-(2-(4-(1-(4,4-dimethyl-2-oxazoline-2-yl)-1-methylethyl) phenyl)piperidine-4-yl]-lH-benzimidazole are dissolved in 30 ml of DMF and to the solution was added 0.54 g of sodium hydride in oil suspense ml ethylchloride. The reaction mass is heated at 70oC for 16 hours, cooled and poured into 300 ml of water. This mixture is extracted with ether and the ether layer washed with water, dried over anhydrous sodium sulfate and filtered. 0.8 g of aluminum hydride and lithium dissolved in 30 ml of ether and to the solution is added dropwise pre-filtered ether phase. The mixture is stirred for 4 hours at room temperature and add 20 ml of 10% sodium hydroxide solution. The mixture is saturated with sodium chloride and the ether layer separated. The aqueous phase is extracted with ether. The ether phase is mixed together and washed with water and saturated sodium chloride solution. This mixture is dried over anhydrous sodium sulfate and concentrated to obtain 2.6 g of 1-(2-hydroxyethyl) -2-[1-(2-(4-(1-(4,4-dimethyl-2-oxazoline-2-yl)-1-methylethyl)phenyl)ethyl)piperidine-4-yl]-1H-benzimidazole in the form of butter.

NMR1H (CDCl3), : 1,3 (C, 6N); 1,6 (C, 6N); 1,8-2,2 (m, 6N); 2,6 (t, 2H); and 2.8 (t, 2H); 2,9 (m, 1H); 3,0-3,1 (m, 2H); 3,7 (s, 2H); 4.0 a (s, 2H); 4,3 (t, 2H); and 7.1 to 7.4 (m, 7H), and 7.7 (m, 1H).

NMR13With (CDCl3), : 15,01; 25,34; 31,07; 33,07; 34,53; 39,78; 43,64; 53,72; 60,52; 66,88; 68,62; 73,07; 109,13; 119,44; 121,77; 121,94; 126,22; 128,80; 134,78; 138,39; 142,71; 143,90; 158,45.

Example 6

Getting 2-[4-(2-(4-(1-(2-hydroxyethyl)benzimidazole-2-yl)-piperid-2-yl)-1-methylethyl)phenyl)ethyl)piperidine-4-yl] -1H-benzimidazole (S) is dissolved in 45 ml of 3h. Model HC1 and heated under reflux for one hour. The solution is brought to a basic pH with 50% NaOH solution and add 20 ml of ethylene glycol. The mixture is heated at 190oWith over three hours with simultaneous distillation and then concentrated in vacuo. Add water and extracted with ether. The aqueous layer was adjusted to pH 7 with dilute solution model HC1, saturated with sodium chloride and extracted with n-butanol. The ethereal extract is dried and concentrated. The residue is recrystallized in acetone/methanol to obtain 2.7 g 2-[4-(2-(4-(1-(2-hydroxyethyl)-benzimidazole-2-yl)piperidine-1-yl)ethyl)phenyl]-2-methylpropanoic acid.

So pl.: 218oC (decomposes)

NMR1H (CDCl3), : 1,4 (C, 6N); 2,0-2,1 (m, 4H); 2,7-2,9 (m, 4H); 2,9-3,1 (t, 2H); of 3.2 to 3.5 (m, 3H); 3,7 (t, 2H); 4,3 (t, 2H); 6,9-7,1 (m, 2H); 7,1-7,2 (m, 2H); 7,2-7,3 (m, 2H); 7.3 to 7.4 (m, 1H); of 7.4-7.5 (m, 1H).

1. Derivatives of benzimidazole of the formula

< / BR>
in which R1represents hydrogen or hydrocarbon group with a short chain, such as methyl, ethyl, isopropyl; and

R2represents a group selected from CH2HE, COOH, R34,4-dimethyl-2-oxazoline, and R3is an alkyl group with a short chain, as defined above, and their additive salts with FA is oxyethyl)-2-[1-(2-(4-(1-(4,4-dimethyl-2-oxazoline-2-yl)-1-methylethyl)-phenyl)ethyl)piperidine-4-yl] -1H-benzimidazole or its additive salt with a pharmaceutically acceptable acid or base.

3. Connection on p. 1, which is 2-[4-(2-(4-(1-(2-ethoxyethyl)benzimidazole-2-yl)piperidine-1-yl)ethyl)phenyl] -2-methylpropanoic acid or its additive salt with a pharmaceutically acceptable acid or base.

4. Connection on p. 1, which is ethyl 2-[4-(2-(4-(1-(2-ethoxyethyl)benzimidazole-2-yl)piperidine-1-yl)ethyl)phenyl] -2-methylpropanoate or additive salt with a pharmaceutically acceptable acid or base.

5. Connection on p. 1, which is 1-(2-ethoxyethyl)-2-[1-(2-(4-(1,1-dimethyl-2-hydroxyethyl)phenyl)ethyl)piperidine-4-yl] -lH-benzimidazole or its additive salt with a pharmaceutically acceptable acid or base.

6. Connection on p. 1, which is 1-(2-hydroxyethyl)-2-[1-(2-(4-(1-(4,4-dimethyl-2-oxazoline-2-yl)-1-methylethyl)-phenyl)ethyl)piperidine-4-yl] -1H-benzimidazole or its additive salt with a pharmaceutically acceptable acid or base.

7. Connection on p. 1, which is 2-[4-(2-(4-(1-(2-hydroxyethyl)benzimidazole-2-yl)piperidine-1-yl)ethyl)phenyl] -2-methylpropanoic acid or pharmaceutical composition, characterized in that it contains effective as antihistamines, the number of one of the compounds according to paragraphs. 1-7 as the active ingredient is mixed with one or more fillers.

9. A method of treating allergic diseases in patients, which includes the introduction of the pharmaceutical composition under item 8 in suitable doses.

 

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< / BR>
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< / BR>
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< / BR>
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< / BR>
in which: R1is hydrogen, CI/C1-C4/ alkylamino,

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B is hydrogen, COR4or SO2R5with the proviso that when B is COR4or SO2R5, R1is other than hydrogen or a cation, and R9different from hydrogen;

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Q is hydrogen, halogen, C1-C4alkoxy or C1-C4the alkyl, possibly substituted by one to three of the following substituents: halogen, C1-C4alkoxy, C1-C4alkylthio or C2-C4alkenyl;

their optical isomers, when R2and R3not the same or when R7and R8unequal;

their tautomers and geometric isomers, and their attached salts of acids, except when R1is salabrasion cation
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