Novel derivatives of benzimidazole exhibiting anithistaminic properties

The present invention relates to new benzimidazole derivatives and their use in the preparation of medicaments for the treatment of allergic conditions. In particular, these new benzimidazole derivatives exhibit antihistaminic H1 activity free of cardiotoxicity.

Benzimidazole derivatives with antihistamine action are known from Spanish patent application 9201 512, for which European Patent No. EP 580 541 has been granted and in which a number of piperidinobenzimidazole derivatives of general formula 2 having antihistaminic and antiallergic effect are described.

The new benzimidazole derivatives are represented by the formula 1. The distinguishing feature of the compounds according to the invention from the compounds known from EP 580 541 is the significance of the R2 substituent on the phenyl ring in the general formula of benzimidazole derivatives. In the compounds described in EP 580 541 this group is a methyl group, whereas in the compounds according to the invention R2 is oxidized functional groups (CH2OH, COOH, COOR3 and 4,4-dimethyl-2-oxazolinyl). The presence of an oxygen-containing functional group causes a change in the properties of these new compounds, among others towards the selective antihistamine H1 activity which the compounds described in EP 580 541 do not possess.

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In compounds possessing an oxidized functional group, an important pharmacological property has been found, which is essentially selective action and a pharmacological profile that stands out from other known antihistamines. The compounds of the invention show almost exclusively the antihistamine H11 anti-pharmacological effect and are free from the effects on other pharmacological receptors, even at doses well above therapeutic doses. Due to their selective action, they are valuable instruments in the treatment of allergic-type conditions, because they can be used without restrictions by people who take other drugs at the same time and in patients with cardiovascular disorders.

It has long been known that histamine plays a very important role in allergic-type diseases such as allergic rhinitis, conjunctivitis, urticaria and asthma; Antihistamines that act at the Hi histamine receptor level are useful in treating these conditions.

The first generation of antihistamines H1 presents numerous harmful effects, such as sedation and dry mouth, which result from their action on the central nervous system and on collinergic receptors.

The search for substances that would not cross the hematoencephal barrier has led to the replacement of earlier antihistamines with their second generation, which does not show side effects associated with their impact on the central nervous system. This new generation of antihistamines, among which terfenadine and astemizole are noteworthy due to their widespread use worldwide, has recently shown its negative aspect in the form of dangerous cardiovascular effects extending to QT space and atrial arrhythmia, which eliminated their use in these cases in which the patient was prone to such disorders or when he was undergoing treatment with substances that may adversely affect his metabolism.

In recent years, attempts have been multiplied to obtain safe and effective antihistamines Hi, which has resulted in several patent applications for pharmaceutical compositions for the treatment of allergic diseases containing antihistamines free of arrhythmia-inducing effects, such as United States Patent Application No. 924 156 ( 03. 08. 92) and International Patent Application No. 95/00480 (05. 01. 95).

The present invention includes a group of new compounds with a benzimidazole structure with strong selective antihistamine Hi activity that have no effect on the central nervous system and the cardiovascular system.

The compounds of the invention are new benzimidazole derivatives of the general formula 1 in which R1 is hydrogen or a hydrocarbon group such as methyl, ethyl, isopropyl, cyclopropyl or vinyl, R2 is a group selected from CH2OH, COOH, COOR3 and 4,4-dimethyl 2-oxazolinyl, R3 is a short chain alkyl group such as methyl, ethyl and isopropyl and their addition salts with pharmaceutically acceptable acids or bases.

In particular, the invention includes compounds such as:

- (2-ethoxyethyl) -2- [1- (2- (4- (1- (4,4-dimethyl-A2-oxazolin-2-yl) -1- (methylethyl) phenyl) ethyl) piperidin-4- yl] -1H-benzimidazole, 2- [4- (2- (4- (1- (2-ethoxyethyl) benzimidazol-2-yl) -piperidin-1-yl) ethyl) phenyl] -2-methylpropionic acid .

Ethyl 2- [4- (2- (4- (1- (2-ethoxyethyl) benzimidazol-2-yl) piperidin-1-yl) ethyl) phenyl] -2-methylpropionate,

- (2-ethoxyethyl) -2- [1- (2- (4- (1,1-dimethyl-2-hydroxyethyl) phenyl) ethyl) piperidin-4-yl] -1H-benzimidazole,

- (2-hydroxyethyl) -2- [1- (2- (4- (1- (4,4-dimethyl-A²-oxazolin-2-yl) -1- (methylethyl) phenyl) ethyl) piperidin-4-yl] -1H-benzimidazole and 2- [4- (2- (4- (1- (2-hydroxyethyl) benzimidazol- 2-yl) -piperidin-1-yl) ethyl) phenyl] -2-methylpropionic acid or their addition salts with a pharmaceutically acceptable acid or base.

The invention also encompasses the use of compounds of formula I for the preparation of medicaments for the treatment of allergic conditions such as allergic rhinitis, conjunctivitis, urticaria and asthma.

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Said new benzimidazole derivatives according to the invention having a substituted oxidized functional group at the phenyl group are characterized by a high selectivity of action and a pharmacological profile clearly different from known antihistamines. In particular, they show almost exclusive antihistamine Hj activity and no effect on other pharmacological receptors. The high selectivity of the compounds of the invention is demonstrated by the inability to significantly antagonize acetylcholine-induced contractions in the isolated guinea pig ileum, even at high concentrations (0.1 mol) (Magnus, Pflltigers, Arch. Ges. Physiol., 102, 123 (1904); O. Arunlakshana and HO shild., Br. J. Pharmacol. 14, 48-58 (1959) and in vivo through the ability to inhibit the growth of histamine-induced permeability of dermal capillaries in rats (P. Lefebvre, J. Salmon, Leconte and Cauwenberge VH, CR Soc. Biol. 156, 183-186 (1962); K. Udaka, Y. Takeuchi and HZ Morat, Proc. Soc. Exp. Biol. Med., 133, 1384-1387 (1970)).

Although the invention relates to the same problem as disclosed in EP 580 541 (antiallergic / antihistaminic activity), however, it is directed to an additional problem - the highly selective H1 antihistamine effect. EP 580 541 presents experimental data regarding only the lack of action on the central nervous system. A high degree of selectivity was demonstrated in the tests for the absence of anticholinergic activity in relation to the invention. Such information is not available in EP 580 541. In addition, the compounds of the invention show no side effects on the central nervous system and cardiovascular functions. Until now, there was no knowledge of the cardiovascular side effects of the compounds described in EP 580 541, while the absence of such side effects has been proven for the compounds covered by this application.

In addition, it should be noted that references to low toxicity in EP 580 541 refer to general toxicity. However, further studies have found that these compounds in animal studies cause an electrocardiogram prolongation of QTc, which is specific for cardiovascular toxicity. The compounds of the invention do not cause any prolongation of QTc, and therefore their pharmacological profile is clearly different from other antihistamines. This unique and unexpectedly beneficial feature makes these compounds useful for administration together with other drugs whose metabolism depends on cytochrome P 450.

It should be emphasized that the compounds of the invention have helped to solve additional problems that have not yet been recognized. High selectivity and no side effect on the cardiovascular system is an unobvious effect resulting from the new structure.

Compounds of the invention can be obtained as follows.

Compounds of formula 1 in which R1 is a short chain alkyl group and R2 is a 4,4-dimethyl-2-oxazolinyl group may conveniently be prepared by the N-alkylation reaction of 2- (4-piperidinyl) -1H-benzimidazole with an alkylating agent of formula 3 wherein X is a group that easily leaves the nucleophilic substitution reactions such as Cl, Br, J, R4SO2, R2SO3 etc. in the presence of an inorganic base such as an alkali metal carbonate or bicarbonate in an organic solvent, followed by a second N-alkylation reaction to give the benzimidazole of formula 4 with the ether of formula XCH₂CH2OR4 where X is as defined above and R4 is a short chain hydrocarbon group such as Me, Et, i-Pr, cyclopropyl, vinyl etc. in the presence of an alkali metal hydride or carbonate. These reactions are illustrated in reaction scheme 1.

Compounds of formula 1 in which R1 is a short chain alkyl group and R2 is a carboxy group may conveniently be prepared as outlined in scheme 2 by hydrolysis of the benzimidazoles of formula 1a with an inorganic acid such as HCl or H2SO4.

Compounds of formula 1 in which R1 is a short chain alkyl group and R2 is a COOR3 group in which R3 is a short chain alkyl group can be prepared as shown in scheme 3 by acid hydrolysis of benzimidazoles of formula la in the presence of the alcohol solvent R3OH conditions for transesterification.

Compounds of formula 1 in which R 1 is a short chain alkyl group and R 2 is a CH 2 OH group can be prepared as shown in Scheme 4, by reducing benidazoles of formula Ib or Ic with a suitable reducing agent such as lithium aluminum hydride.

Compounds of formula 1 in which R 'is hydrogen and R2 is a 4,4-dimethyl-2-oxazolinyl group can be prepared as outlined in scheme 5, by alkylation of benzimidazole of formula 4 with ethyl chloroacetate in the presence of an alkali metal hydride or carbonate an ester of formula 5 which is then reduced by a reducing agent such as lithium aluminum hydride.

Compounds of formula 1 in which R1 is hydrogen and R2 is a COOH group are conveniently prepared as outlined in scheme 6 by hydrolysis of the compound of formula 1e with an inorganic acid such as HC1 or H2SO4.

The new benzimidazoles of the formula I obtained can be converted into pharmaceutically acceptable addition salts by treatment with appropriate acids or bases.

The examples below illustrate the method of the invention without however limiting its scope.

Example 1

Preparation of 1- (2-ethoxyethyl) -2- [1- (2- (4- (1- (4,4-dimethyl-A²-oxazolin-2-yl) -1- (methylethyl) phenyl) ethyl) piperidin-4-yl] -1H-benzimidazole (1a, R1 = Et)

3.57 g of sodium carbonate were added to the suspension of 14 g of 2- (4- (1- (4,4-dimethyl-D2-oxazolin-2-yl) -1- (methylethyl) phenyl) ethyl p-toluenesulfonate and 6.78 g 2- (4-piperidinyl) -1H-benzimidazole in 60 ml DMF and the resulting suspension was heated at 80 ° C. for 14 hours. DMF was concentrated and the reaction mass poured onto water / ice, after which the crystallized solid was filtered off, washed with water and dried at 50 ° C to give 2- [1- (2- (4- (1- (4,4-dimethyl-Δ²-oksazolin-2-yl) -1- (methylethyl) phenyl) ethyl) piperidin-4-yl] -lH-benzimidazole. The resulting suspension was stirred at room temperature for 2 hours and 2.44 g of 2-chloroethyl ethyl ether was added. The reaction mixture was heated at 80 ° C for 16 hours, cooled, poured onto water / ice, extracted with ether and washed with water and saturated sodium chloride solution. The ether solution was dried over anhydrous sodium sulfate and concentrated to give 11.2 g of 1- (2-ethoxyethyl) -2- [1- (2- (4- (1- (4,4-dimethyl-A ²-oxazolin-2-yl) -1- (methylethyl) phenyl) ethyl) piperidin-4-yl] -1H-benzimidazole; mp: 98-100 ° C (from ethanol).

1 H-NMR (CDCU), J: 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, 1H); 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, 1H).

ⁿC-NMR (CDCl3), J: 14.96; 27.38; 28.15; 31.06; 33.10; 34.53; 40.18; 43.60; 53.71; 60.46; 66.74; 66.83; 68.19; 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 II

Preparation of 2- [4- (2- (4- (1- (2-ethoxyethyl) benzimidazol-2-yl) piperidin-1-yl) ethyl) phenyl] -2-methylpropionic acid (1b, R '= Et)

6.72 g 1- (2-Ethoxyethyl) -2- [1- (2- (4- (1- (4,4-dimethyl-D2-oxazolin-2-yl) -1- (methylethyl) phenyl) ethyl ) piperidin-4-yl] -1H-benzimidazole (formula 1a) was dissolved in 170 ml of 3N HCl and refluxed for one hour. The reaction mixture was cooled and adjusted to pH 7 with 50% sodium hydroxide. The solution was extracted -butanol, washed with water, dried over anhydrous sodium sulfate and concentrated. Methanol (30 ml) and 50% sodium hydroxide (40 ml) were added to the residue and refluxed for 30 minutes. Methanol was distilled off and water was added until completely dissolved. It was extracted with ether and the aqueous layer adjusted to pH 7 with 20% HCl and saturated with sodium chloride, then the precipitated solid was filtered off, washed several times with water and dried in a vacuum dryer at 50 ° C to obtain 3.5 g of 2- [4] acid - (2- (4- (l- (2-ethoxyethyl) benzimidazol-2-yl) piperidin-1-yl) ethyl) phenyl] -2-methylpropanoic acid; M.p .: 199-201 ° C.

NM-NMR (DMSO-de), J: 1.0 (t, 3H); 1.4 (s, 6H); 1.8 (m, 4H); 2.2 (m, 2H); 2.5 (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).

188 908 ¹³C-NMR (DMSO-de), J: 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 III

Preparation of ethyl 2- [4- (2- (4- (1- (T-ethoxyethyl) benzimidazol-2-yl) piperidin-1-yl) ethyl) phenyl] -2-methylpropionate (1c, R1 = Et, R3 = et).

Concentrated sulfuric acid (20 ml) was added to the solution 10 g 1- (2-ethoxyethyl) -2- [1- (2- (4- (1- (4,4-dimethyl-A²-oxazolin-2-yl) -1- (methylethyl) phenyl) ethyl) piperidin-4-yl] -1H-benzimidazole in 250 ml ethanol and refluxed for 16 hours, then cooled and added 1 liter of ether. The organic layer was separated and washed with water, 10% sodium bicarbonate solution and once more with water, then dried over anhydrous sodium sulfate and concentrated to give 7 g of oil, which was purified by flash chromatography using a 95/5 chlorotorm / methanol mixture as eluent to obtain 5 g Ethyl 2- [4- (7- (4- (1- ((2-ethoxyethyl) berizimidazo-2-yl) piperidin-1-yl) ethyl) phenyl] -2-methylpropionate as an oil.

1 H-NMR (CDCl 3), J: 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, 1H); 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); 7.6-7.7 (m, 1H).

13 C-NMR (CDCl 3), J: 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 IV

Preparation of 1- (2-ethoxyethyl) -2- [1- (2- (4- (1,1-dimethyl-2-hydroxyethyl) phenyl) ethyl) piperidin-4-yl] -11-berzimidazole (1d, R1 = Et) g of lithium aluminum hydride was dissolved in 30 ml of THF and 3 g of 2 [4- (2- (4- (1- (2-ethoxyethyl) benzimidazol-2-yl) piperidin-1-yl) ethyl was added dropwise thereto. ) ethyl phenyl] -2-methylpropionate. The mixture was stirred for 4 hours at room temperature and a few ml of water added to remove excess hydride. The solution was filtered and the filtrate was washed with saturated sodium chloride solution. Then dried and concentrated. The residue was redissolved in chloroform and washed with water, dried and concentrated. The residue was purified by flash chromatography using a 2 / 7.5 / 0.5 hexane / ether / isopropylamine mixture 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] -1H-benzimidazole; Mp: 112-114 ° C.

1 H-NMR (CDCl 3), J: 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, 1H); 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, 1H).

¹³C-NMR (CDCl 3), J: 15.01; 24.34; 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 V

Preparation of 11-2-hydroxy-yoyl ^ -f [1-2-4- (1 L-4,4-dimethyl-D²-oksazotm-2-ylot) ll

- (methylethyl) phenylk) ethyl) -piperidin-4-yl] -1H-benzimidazolo (1e).

g 2- [1- (2- (4- (1- (4,4-dimethylk-D - oxazolin-2-yl) -1- (methylethyl) phenyl) piperidin-4-yl] -1H-benzimidazole was dissolved in 30 ml DMF and 0.54 g of sodium hydride suspended in oil added thereto. The resulting suspension was stirred for 2 hours at room temperature and in Sprplork 1.19 ml of ethyl chloroacetate. The reaction mass was heated at 70 ° C for 16 hours, cooled and poured into 300 ml of water. It was then extracted with ether and the ether layer was washed with water, dried over anhydrous sodium sulfate and filtered. 0.8 g of lithium aluminum hydride was dissolved in 30 ml of ether and the previously filtered ether phase was melted into this solution. The mixture was stirred for 4 hours at room temperature and 20 ml of a 10 O O hydroxide solution added to it. Colo? 1 was saturated with sodium cork and the ether layer separated. The aqueous phase was extracted with ether. All ether phases were mixed together and washed with water and saturated sodium chloride solution. It was then washed over anhydrous sodium sulfate and concentrated to give 1- (2-hydroxy-188 908) -2- [1- (2- (4- (1- (4,4-dimethyl-D²-oxazolin-2-yl) -1- (methylene) p-phenyl) -elyl) oil, n-4-yl] -1H-benzimidazole in the form of oil.

1 H-NMR (CDCl 3), J: 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 1H); 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, 1H).

^r3C-NMR (CDCl 1), J: 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 VI

Preparation of 2- [4- (2- (4- (1- (2-hydroxyethyl) benzimidazol-2-yl) piperidin-1-yl) ethyl) phenyl] -2-methylpropionic acid (1 f) g 1- (2 -hydroxyethyl) -2- [1- (2- (4- (1- (4,4-dimethyl-A2-oxazolin-2-yl) -1- (methylethyl) phenyl) ethyl) piperidin-4-yl] -1H-benzimidazole (1e) was dissolved in 45 ml 3N HCl and refluxed for an hour, then brought to basic pH with 50% NaOH and 20 ml ethylene glycol was added. The whole was heated at 190 ° C for 3 hours with simultaneous distillation, and then concentrated in vacuo. Water was added and extracted with ether. The aqueous layer was adjusted to pH 7 using a solution of dilute HCl, saturated with sodium chloride and extracted with n-butanol. The ether extract was dried and concentrated. The residue was recrystallized in acetone / methanol to give 2.1 g of 2- [4- (2- (4- (1- (2-hydroxyethyl) bernzimidazol-2-yl) piperidin-1-yl) ethyl) phenyl] -2- propionic acid methyl ester; T. mp: 218 ° C (decomposition).

NM-NMR (CDCl3), J: 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, 1H); 7.4-7.5 (m, 1H).

Based on the conducted pharmacological studies, it was proved that the compound of formula 1b (R1 = ethyl) is a strong mixed histamine H1 receptor antagonist in the ileum of guinea pig, with calculated pA2 = 7.98-8.10 and pD '2 = 6.50 . The same compound inhibited in vivo the increase in capillary permeability in rats at DE50 close to 2 mg / kg po. At doses of 5 mg / kg po, it maintained significant activity exceeding 50% for at least 6 hours.

The compounds of the invention have a highly selective pharmacological effect and present no significant anticholinergic activity and no effect on the central nervous system and the cardiovascular system. The in vivo tested compound of formula 1b (R1 = Et) is not able to significantly antagonize acetylcholine-induced contractions in the isolated guinea pig ileum at 0.1 molar concentrations and does not modify spontaneous motor activity in a rat at a dose of 100 mg / kg po; in addition, the same compound administered at a dose of 20 mg / kg iv does not induce any ECG morphological interference or increase QT intervals in rats.

Because of their useful pharmacological antihistamine and antiallergic properties, several pharmaceutical forms may be prepared from the compounds of the present invention for subsequent oral, topical, injection and rectal administration. Oral preparations are prepared by thoroughly mixing an antihistamine effective amount of one of the compounds of the invention with excipients such as lactose, cellulose, talc and the like for tablets or capsules or with excipients such as water, glycols, alcohols, oils and the like for syrups, solutions and suspensions. The form for topical administration may be prepared in the form of creams, ointments, gels, solutions and transdermal patches, using agents such as petroleum jelly, polyethylene glycols, etc. as carriers. In the injectable preparations, the excipient will, at least for the most part, be sterilized water, although other excipients such as saline solutions, glucose solutions etc. or mixtures thereof may be added to increase solubility.

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188 908

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formula 2

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DIAGRAM 1

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ABOUT

Oh u

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in_ZÓ1 · La ^pattern&lt;· ^1b

188 908

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formula 1d

DIAGRAM 3

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188 908

DIAGRAM 5

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^{formula 1c} formula 1f

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