Benzimidazole derivatives with antihistaminic activity

DESCRIPTION

New derivatives of benzimidazole with antihistamlnica activity.

Object of the invention

The present invention relates to new benzimidazole derivatives with antihistamine H1 activity, devoid of cardiotloxic effects.

Background of the invention

The compounds of the present invention have their closest antecedents in Spanish Patent No. 9201512, in which a series of piperidine derivatives of benzimidazole with antihistamolytic and anti-allergic activities of the general formula are described:

<img file="ES2124167B1_D0001.tif" />

The compounds described in this Report have a fundamental structural difference with respect to those of the mentioned patent and it is the presence of oxygenated functions in the substitution on the phenyl group, for which, on the other hand, an important pharmacophoric caraócter has been found, which results in the compounds that contain them, consequently, some pharmacological characteristics that are different from those of the antihistamolines known so far and which focus primarily on the selectivity of action, since the compounds referred to in this Report have almost exclusively H1 antihistamolytic activity, being devoid of action on other dose receptors even far superior to the therapeutic ones. This selectivity of action makes them valuable instruments in the treatment of allergic type processes, allowing, in particular, their use without restrictions by people receiving any other concomitant medication, just as in the case of patients with pathological disorders at the cardiocirculatory level. .

Description of the invention

It has been known for a long time that histamine has a very important role in allergic diseases, such as allergic rhinitis, conjunctivitis, urticaria and asthma, so that the antihistamine compounds that act at the level of the H1 receptors of histamine are useful in the treatment of these processes.

The first generation H1 antihistamolines had a number of adverse effects, such as sedation and dry mouth, as a result of their action on the central nervous system and cholinergic receptors.

The search for molecules that did not cross the blood-brain barrier resulted in the displacement of antihistamolytic primitives by others of the second generation that obviated the side effects associated with the action on the central nervous system. This new generation of antihistaminics, which include terfenadine and astemizole worldwide, has recently shown a negative aspect in the form of dangerous cardiovascular effects, with lengthening of the QT space and ventricular arrhythmias, what has forced to avoid its use in those cases in which the patient is prone to suffer such alterations or when he is treated with substances that may interfere with his metabolism.

Attempts to obtain safe and effective H1 antihistaminics have multiplied in recent years and, as a result of these investigations, some patents have recently been applied for in claiming for the treatment of allergic diseases pharmaceutical compositions containing antihistaminics lacking arrhythmogenic effects , as in US patent application n^° 924.156 (08/3/92) and in international patent n^° 95/00480 (05/01/95).

The present invention relates to a group of new compounds with benzimidazole structure with potent and selective antihistamolytic H1 activity and lacking activity on the central nervous system

ES 2 124 167 B1 and on the cardiovascular system.

The compounds covered by the present invention have as a general formula:

<img file="ES2124167B1_D0002.tif" />

in which R₁ is hydrogen or a short chain carbon group such as methyl, ethyl, isopropyl, cyclopropyl or vinyl, and R2 is a group selected from CH2 OH, COOH, COOR3 and 4,4-dimethyl-2oxazolinyl, where R₃ a short chain alkyl group as defined above, as well as its additional salts with pharmacologically acceptable acids or bases.

Compounds I in which R1 is a short chain alkyl group and R2 is the 4,4-dimethyl2-oxazolinyl group can be conveniently prepared by an N-alkylation reaction of 2- (4piperidinyl) -1H-benzimidazole with an agent type III alkylating agent where X is m good leaving group in nucleophilic substitution reactions such as Cl, Br, I, R4SO2, R5SO3 etc., in the presence of a base of inorgaonic nature, such as m carbonate or alkali metal bicarbonate in an orgaonic solvent, followed by a new N-alkylation reaction of the resulting benzimidazole IV with an XCH type ether₂CH₂OR₁, where X has the significance previously summarized and R₁ it is m short chain carbon group, such as Me, Et, i-Pr, cyclopropyl, vinyl, etc., in the presence of a hydride or an alkali metal carbonate.

<img file="ES2124167B1_D0003.tif" />

Compounds I, in which R1 is a short chain alkyl group and R2 is a carboxyl group, can be conveniently prepared by hydrolysis of benzimidazoles Ia with a mineral acid such as HCl or H2SO4.

ES 2 124 167 B1

<img file="ES2124167B1_D0004.tif" />

Compounds I in which R1 is a short chain alkyl group and R2 is a COOR3 group in which R₃ it is a short chain alkyl group, they can be prepared by an acid hydrolysis of the benzimidazoles Ia in the presence of an alcoholic solvent R₃OH, under adequate conditions for transesterification to take place.

<img file="ES2124167B1_D0005.tif" />

such as lithium aluminum hydride.

<img file="ES2124167B1_D0006.tif" />

by an alkyl benzimidazole IV with ethyl chloroacetate in the presence of an alkali metal hydride or carbonate to give the ester V, which is then reduced by a reducing agent such as lithium aluminum hydride.

<img file="ES2124167B1_D0007.tif" />

ES 2 124 167 B1

Compound I in which R1 is a hydrogen and R2 is a COOH group is conveniently prepared by hydrolysis with a mineral acid such as HCl or H2SO4 of compound Ie.

<img file="ES2124167B1_D0008.tif" />

The new benzimidazoles I obtained can be transformed into pharmaceutically acceptable salts by treatment with appropriate acids or bases.

The compounds of formula I have useful pharmacological properties. More particularly, they are potent antihistamines H₁. This activity has been clearly demonstrated “in vitro” by the blockage of histamine-induced contractions in guinea pig isolated laron (Magnus, Pflugers, Arch. Ges. Physiol., 102, 123 (1904); Arunlakshana, O. and Schild, HO, Br. J. Pharmacol. 14, 48-58 (1959)), and "in vivo" for the ability to inhibit the increase in histamine-induced cutaneous capillary permeability in rats (Lefáebvre, P., Salmon, J., Leconte and Cauwenberge, VH, CR Soc. Biol. 156, 183-186 (1962); Udaka, K., Takeuchi, Y. and Morat, HZ, Proc. Soc. Exp. Biol. Med. 133, 1384-1387 (1970)).

Thus, for example, compound Ib (R1 = ethyl) was shown as a potent mixed antagonist of the H1 histamine A receptors present in the guinea pig wing, calculating a pA2 = 7.98-8.10 and a pD2 '= 6, fifty. This same compound in the "in vivo" test significantly inhibited the increase in capillary permeability in rats with an ED50, close to 2 mg / kg po At the dose of 5 mg / kg po maintained a significant activity, greater than 50 %, for at least 6 hours.

These compounds are highly selective in their pharmacological action, not presenting significantly anticholinergic activity or on the central and cardiovascular nervous systems. Thus, compound Ib (R1 = Et) at 0.1 M concentrations shows no ability to significantly antagonize acetylcholine-induced contractions in isolated guinea pig and at doses of 100 mg / kg po does not modify the spontaneous motor activity of the mouse; also this same compound, administered at doses of 20 mg / kg iv does not induce any morphological alteration of the ECG or increase the QT interval of rats.

In view of their useful pharmacological properties as antihistamanic and anti-allergic, the compounds described in the present invention can be formulated in various pharmacological forms for later administration by oral, topical, injectable and rectal route. Preparations by oral route are made by intimately mixing an effective amount as antihistamanic of one of the products described in the present invention with excipients such as lactose, cellulose, talc and the like for tablets or capsules, or water, glycols, alcohols, oils and the like for syrups, solutions and suspensions. Administration by the tactic route can be done in the form of creams, ointments, gels, solutions and transdermal patches, using as support agents such as petrolatum, polyethylene glycols, etc. In injectable preparations the excipient will be, at least for the most part, sterilized water although, to help solubilize, other excipients, such as saline solutions, glucose solutions, etc., or mixtures thereof may be added.

The examples that are detailed below illustrate the present invention without limiting its scope in any way.

Example 1

Preparation of 1- (2-ethoxyethyl) -2- [1- (2- (4- (1- (4.4 ~ dimethyl ~ ^²-oxazolin-2-yl) -1-methylethyl) phenyl) ethyl) piperidin4-yl] -1 H -benzimidazole. (Ia, R1 = Et)

On a solution of 14 g of p-toluenesulfonate of 2- (4- (1- (4,4-dimethyl ^²-oxazolin-2-yl) -1-methylethyl) phenyl) ethyl and 6.78 g of 2- (4-piperidinyl) -1H-benzimidazole in 60 ml of dimethylformamide add 3m57 g of sodium carbonate and the resulting suspension is heated at 800 for 14 hours. The dimethylformamide is concentrated and the reaction mass is poured onto water / ice crystallizing a saolide that

ES 2 124 167 B1 is filtered, washed with water and dried at 50 ° C to obtain 10 g of 2- [1- (2- (4- (1- (4,4-dimethyl ^²-oxazolin2-yl) -1-methylethyl) phenyl) ethyl) piperidin-4-yl] -1H-benzimidazole. The solid obtained is dissolved in 25 ml of dimethylformamide and 1.2 g of a suspension of 60% paraffin sodium hydride are added. The resulting suspension is stirred at room temperature for two hours and 2.44 g of 2-chlorethylethylether are added. The reaction mass is heated at 80 ° C for 16 hours, cooled and poured onto water / ice. It is extracted with ether and washed with water and with saturated sodium chloride solution. Dry over anhydrous sodium sulfate and concentrate to obtain 11.2 g of 1- (2-ethoxyethyl) -2- [1- (2- (4- (1- (4,4-dimethylΔ)²-oxazoliñ-2-yl) -1-methylethyl) phenyl) ethyl) piperidiñ-4-yl] -1H-beñimimidazole.

PF 98-100^°C (ethanol).

NMR-¹H (CDCl3) δ: 1.1 (t, 3H); 1.3 (s, 6H); 1.5 (s, 6H); 1.9 (m, 2H); 2.1 (m, 4H); 2.6 (t, 2H); 2.8 (t, 2H); 3.0 (m, 1 H); 3.1 (d, 2H); 3.4 (c, 2H) 3.7 (t, 2H); 3.9 (s, 2H) 4.3 (t, 2H); 7.1-7.3 (m, 7H); 7.7-7.8 (m, 1 H).

NMR-¹³C (CDCl3) δ: 14.96; 27.38; 28.15; 31.06; 33.10; 34.53; 40.18; 43.60; 53.71; 60.46; 66.74; 66.83; 68.59; 79.14; 109.09; 119.41; 121.71; 121.88; 125.30; 128.73; 134.78; 138.72; 142.72; 143.04; 158.41 and 177.70.

Example 2

Preparation of 2- [4- (2- (4- (T (2-ethoxyethyl) benzimidazol-2-yl) piperidin-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-oxazolin-2-yl) -1-methylethyl) phenyl) ethyl) piperidin-4-yl] -1 H -benzinidazole (Ia) in 170 ml of 3N HCl and heated at reflux for one hour. It is cooled and brought to pH 7 with 50% sodium hydroxide. Cm n-butanol is extracted. Wash cm water. It is dried over anhydrous sodium sulfate and concentrated. 30 ml of methanol and 40 ml of 50% sodium hydroxide are added on the residue and heated at reflux for thirty minutes. The methanol is distilled and diluted with water until completely dissolved. It is extracted with ether and the aqueous layer is brought to pH 7 with 20% HCl and saturated with sodium chloride precipitating a filtering solid, washed with water repeatedly and dried in a vacuum oven at 50^°C obtaining 3.5 g of 2- [4- (2- (4- (1- (2-ethoxyethyl) benzimidazol-2-yl) piperidin-1-yl) ethyl) phenyl] -2-methylpropanoic acid.

PF: 199-201^°C

NMR-¹H DMSO-d6), δ: 1.0 (t, 3H); 1.4 (s, 6H); 1.8 (m, 4H); 2.2 (m, 2H); 2.5 (t, 2H); 2.7 (t, 2H); 3.0 (m, 3H);

3.3 (c, 2H); 3.6 (t, 2H); 4.4 (t, 2H); 7.0-7.3 (m, 6H); 7.4-7.6 (m, 2H).

NMR-¹³C (DMSO-d6), δ: 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; 121.35; 125.47; 128.42; 134.72; 138.33; 142.29; 143.03; 158.60; and 177.87.

Example 3

Preparation of ethyl 2- [4- (2- (4- (1- (2-ethoxyethyl) benzimidazol-2-yl) piperidin-1-yl) ethyl) phenyl] -2-methylpropanoate. (Ic, R1 = Et, R3 = Et)

10 g of 1- (2-ethoxyethyl) -2- [1- (2- (4- (1- (4,4-dimethyl ^)²-oxazolin-2-yl) -1-methylethyl) phenyl) ethyl) piperidin-4-yl] -1 H -benzimidazole in 250 ml of ethanol, 20 ml of concentrated sulfuric acid are added and heated under reflux for 16 hours. It is cooled and 1 liter of ether is added. The organic layer is separated and, washed with water, 10% solution of sodium bicarbonate and again with water. It is dried over anhydrous sodium sulfate and concentrated to obtain 7 g of an oil which is purified by flash chromatography using as eluent a 95/5 chloroform / methanol mixture. 5 g of ethyl 2- [4- (2- (4- (1- (2ethoxyethyl) benzimidazol-2-yl) piperidin-2-yl) ethyl) phenyl] -2-methylpropanoate are obtained as an oil.

NMR-¹H (CDCl3), δ: 1.1 (t, 3H); 1.2 (t, 3H); 1.5 (s, 6H); 2.0 (m, 2H) 2.2 (m, 4H); 2.6 (t, 2H); 2.8 (t, 2H); 3.0 (m, 1 H); 3.2 (m, 2H); 3.4 (c, 2H); 3.7 (t, 2H); 4.1 (c, 2H); 4.3 (t, 2H); 7.1-7.3 (m, 7H); 7.67.7 (m, 1 H).

NMR-¹³C (CDCl3), δ: 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.

ES 2 124 167 B1

Example 4

Preparation of 1- (2-ethoxyethyl) -2- [1- (2- (4- (1,1-dimethyl-2-hydroxyethyl) phenyl) ethyl) piperidin-4-yl] -1H-benzimidazole. (Id, R1 = Et)

1 g of lithium aluminum hydride is dissolved in 30 ml of tetrahydrofuran and 3 g of 2- [4- (2- (4- (1- (2-ethoxyethyl) benzimidazol-2-) are added dropwise ethyl ilpiperidin-1-yl) ethyl) phenyl] -2-methylpropanoate, stir four hours at room temperature and add a few milliliters of water to remove excess hydride, filter and the filtrate is washed with saturated solution of sodium chloride, dried and concentrated, the residue is redissolved in chloroform and washed with water. It dries and concentrates. The residue is purified by flash chromatography using a mixture of hexane / ether / isopropylmia (2 / 7.5 / 0.5) as eluent to obtain 1.5 g of 1- (2-ethoxyethyl) -2- [1- ( 2- (4- (1,1-Dimethyl-2-hydroxyethyl) phenyl) ethyl) piperidin-4-yl] 1 H -benzimidazole.

PF: 112-114 ° C

NMR-¹H (CDCl3), δ: 1.0 (t, 3H); 1.4 (s, 6H); 1.9-2.1 (m, 2H); 2.1-2.3 (m, 4H); 2.6 (t, 2H); 2.8 (t, 2H); 3.0 (m, 1 H); 3.2 (d, 2H); 3.4 (c, 2H); 3.6 (s, 2H); 3.7 (t, 2H); 4.3 (t, 2H); 7.1-7.4 (m, 7H); 7.8 (m, 1 H).

NMR-¹³C (CDCl3), δ: 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

Preparation of 1- (2-hydroxyethyl) -2- [1- (2- (4- (1- (4,4-dimethyl ^²-oxazolin-2-yl) -1-methylethyl) phenyl) ethyl) piperidin-4-yl] -1H-benzimidazole. (Ie)

5g of 2- [1- (2- (4- (1- (4,4-dimethyl-D)²-oxazolin-2-yl) -1-methylethyl) phenyl) ethyl) piperidin-4-yl] -1Hbenzimidazole in 30 ml of DMF and 0.54 g of a suspension of paraffin sodium hydride are added. The resulting suspension is stirred for two hours at room temperature and 1.19 ml of ethyl chloroacetate is dripped. The reaction mass is heated at 700 for 16 hours, cooled and poured onto 300 ml of water. It is extracted with ether and the ether layer is washed with water, dried over anhydrous sodium sulfate and filtered. 0.8 g of lithium aluminum hydride are dissolved in 30 ml of ether and the previously filtered ether phase is dripped onto this solution. It is stirred for 4 hours at room temperature, and 20 ml of a 10% sodium hydroxide solution is added. It is saturated with salt and the ether layer is separated. The aqueous phase is extracted with ether. All the etheric phases are combined and washed with water and saturated sodium chloride solution. Dry over anhydrous seodic sulfate and concentrate to obtain 2.6 g of 1- (2-hydroxyethyl) -2 [1- (2- (4- (1- (4,4-dimethyl ^²-oxazolin-2-yl) -1-methylethyl) phenyl) ethyl) piperidin-4-yl] -1 H -benzimidazole as an oil.

NMR-¹H (CDCl3), δ: 1.3 (s, 6H); 1.6 (s, 6H); 1.8-2.2 (m, 6H); 2.6 (t, 2H); 2.8 (t, 2H); 2.9 (m, 1 H); 3.0-3.1 (m, 2H); 3.7 (s, 2H); 4.0 (s, 2H); 4.3 (t, 2H); 7.1-7.4 (m, 7H); 7.7 (m, 1 H).

NMR-¹³C (CDCl3), δ: 109.13; 119.44; 121.77;

15,01; 25,34; 31,07; 33,07; 34,53; 39,78; 43,64; 53,72; 60,52; 66,88; 68,62; 73,07 121,94; 126,22; 128,80; 134,78; 138,39; 142,71; 143,90; 158,45.

Example 6

Preparation of 2- [4- (2- (4- (1- (2-hydroxyethyl) bencindazol-2-yl) piperidin-1-yl) ethyl) phenyl] -2-methylpropanoic acid. (If)

5 g of 1- (2-hydroxyethyl) -2- [1- (2- (4- (1- (4,4-dimethyl ^)²-oxazolin-2-yl) -1-methylethyl) phenyl) ethyl) piperidin-4-yl] -1H-benzimidazole. (Ie) in 45 ml of 3N HCl and heated at reflux for one hour. It is brought to basic pH with 50% NaOH and 20 ml of ethylene glycol are added. It is heated at 190 ° C for three hours with simultaneous distillation and then concentrated in vacuo. It is added, water and extracted with ether. The aqueous layer is brought to pH 7 with dilute HCl. It is saturated with sodium chloride and extracted with n-butanol. It dries and concentrates. The residue is recrystallized from acetone / methanol to give 2.7 g of 2- [4- (2- (4- (1- (2-hydroxyethyl) benzimidazol-2-yl) piperidin-1-yl) ethyl) phenyl ] -2-methylpropanoic.

PF: 218^°C (decomposes)

NMR-¹H (CD3OD), δ: 1.4 (s, 6H); 2.0-2.1 (m, 4H); 2.7-2.9 (m, 4H); 2.9-3.1 (t, 2H); 3.2-3.5 (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); 7.3-7.4 (m, 1 H); 7.4-7.5 (m, 1 H).

ES 2 124 167 B1