ES2246742B1 - USE OF A DERIVATIVE OF IMIDAZOLE. - Google Patents

Abstract

Use of an imidazole derivative of formula (I),

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100

(I)

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where

- R1 is a hydroxy radical; I rent; alkoxy; cycloalkyl; cycloalkoxy; or optionally substituted carboxy;

- R2 is a carboxy group; alkoxycarbonyl; or a optionally substituted phenyl group;

- R3 is a hydrogen or halogen atom; a hydroxy radical; carboxy; I rent; hydroxyalkyl; alkoxy; cycloalkyl; cycloalkoxy; Not me; alkylthio; cycloalkylthio; aryl; heteroaryl; aryloxy; heteroaryloxy; arylthio; or heteroarylthio optionally substituted;

- R4 is a hydroxy radical; hydroxyalkyl; alkoxy; cycloalkyl;

cycloalkoxy; Not me; alkylamino; carboxy; I rent; alkenyl; aryl; heteroaryl; aryloxy; or heteroaryloxy optionally substituted; or

- R3 and R4, together with the atoms of the imidazole ring to which they are attached, benzimidazole, imidazopyridine, imidazopyrimidine, thienoimidazole, imidazopyrazole, imidazopyridone or imidazopyridazinone;

or one of its salts or solvates physiologically acceptable, for the manufacture of drugs for the treatment of disorders mediated by leukotrienes or peptidoleukotrienes.

Description

Use of an imidazole derivative.

Technical sector to which the invention relates

The present invention relates to the use of imidazole derivatives of general formula (I),

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1

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as well as its salts or solvates physiologically acceptable, in the manufacture of medicines, useful in human therapeutics, for the treatment of disorders mediated by leukotrienes or peptidoleukotrienes, by example LTD 4, such as certain disorders of the respiratory, cardiovascular, digestive, genitourinary, nervous, musculoskeletal, skin conditions or some types of Cancer.

State of the art of the invention

The use of inhaled corticosteroids in the treatment of asthmatic processes presents, despite its efficacy, some unwanted effects as well as toxicity, mostly in children. Furthermore, in a good number of patients, control is not achieved. desired therapeutic need, so it is important to find new anti-asthmatic agents that have fewer effects secondary. One of the new therapeutic approaches is the use of peptidoleukotriene antagonists, which in addition to their bronchodilator potential also show activity anti-inflammatory.

Most leukotrienes are derived from arachidonic acid, a fatty acid that is released from the phospholipid that contains it by the action of phospholipase A 2. Arachidonic acid is in turn metabolized mainly by two different enzyme systems. One, through cyclooxygenase, produces thromboxane and prostaglandins, mediators of inflammation, but which also participate in functions such as muscle contraction, calcium transport, hormonal regulation and control of cell growth. The other, through lipoxygenases, produces hydroxyeicosateraenoic acids and leukotrienes, the most important of the latter being the leukotriene LTB4 and the peptidoleukotrienes LTC4, LTD4 and LTE4 (Higgs et al . Annals of Clinical Research 16, 287 (1984)). All of them also participate in the inflammatory reaction, being considerably involved in immediate hypersensitivity reactions (Bayley and Casey, Ann. Rep. Med. Chem., 17, 203 (1982)).

LTD4 is a potent bronchoconstrictor, while it induces smooth muscle contraction, myocardial depression, increased vascular permeability and mucus production (Marom et al ., Am. Rev. Resp. Dis., 126 , 449 (1982)), so it is directly involved in the pathogenesis of:

- Bronchial asthma (Dalen et al ., Nature, 288, 484 (1980); Kemp, Idrugs, 3, 430 (2000)).

- Allergic rhinitis (Steinke and Borish, Curr Allergy Asthma Rep, 4, 217 (2004); Brusse and Kraft, Chest, 127, 1312 (2005)).

- Chronic bronchitis (Bisgaard, Am J Respir Crit Care Med, 167, 379 (2003)).

- Chronic pulmonary obstructive disease (Brusse et al ., Clin Exp Allergy, 29, 110 (1999); Molfino, Respiration, 72, 105 (2005)).

In addition, both LTC4 and LTD4 induce exaggerated contraction in cardiac tissue, which has suggested their involvement in situations of cardiac anaphylaxis (Marone et al ., Int Arch Allergy Immunol, 107,72 (1995), endotoxic shock (Cinar et al ., Eur J Pharmacol, 350, 223 (1998), or cerebral edema (Di Gennaro et al ., FASEB J, 18, 842 (2004)).

It has also been convincingly demonstrated the importance of leukotriene LTD4 in numerous pathologies related to inflammatory processes. There is abundant evidence experimental and clinical that describes the important role that LTD 4 receptor blocking drugs can play as therapeutic weapon in the treatment of these conditions:

- Arthritis (Mohillo and McCarthy, Curr Opin Rheumatol, 17, 346 (2005); Sulliva, Pediatr Clin North Am, 52, 335 (2005)).

- Eosinophilic sinusitis (Steinke and Borish, Curr Allergy Asthma Rep, 4, 217 (2004); Corrigan et al ., J Allergy Clin Immunol, 115, 316 (2005)).

- Otitis media (Tada et al ., Auris Nasus Larynx, 29, 127 (2002)).

- Chronic urticaria (Sanada et al ., Arch Dermatol Res, 26; 1 (2005); Sanada et al ., Arch Dermatol Res, 26, 1 (2005)).

- Nasal polyposis (Gillespie and Osguthorpe, Curr Allergy Asthma Rep, 4, 478 (2004); Bachert et al ., Drugs, 65, 1537 (2005)).

- Atopic dermatitis (Rackal and Vender, Skin Therapy Lett, 9, 1 (2004); Hon et al ., J Dermatolog Treta, 16, 15 (2005)).

- Allergic conjunctivitis (Lambiasc et al ., Arch Ophtalmol, 121, 615 (2003); Papathanassiou et al ., Inflamm Res, 53, 373 (2004)).

- Eosinophilic gastroenteritis (Sener et al ., Prostagalndins Leukot Essent Fatty Acids, 72, 1 (2005); Quack et al ., BMC Gatroenterol, 18, 5 (2005); Reims et al ., Scand J Gastroenterol, 41, 160 ( 2005)).

- Irritable bowel syndrome (Fee, Chest, 122, 1497 (2002)).

- Mastocytosis (Tolar et al ., N engl J Med, 350, 735 (2004)).

- Idiopathic pulmonary fibrosis (Brock et al ., Am J Physiol Lung Cell Mol Physiol, 289, L224 (2005)).

- Cardiac fibrosis (Levick and Brown, Cardiovasc J S Afr, 15, S8 (2004)).

- Multiple sclerosis (Neu et al ., Acta Neurol Scand, 105, 63 (2002)).

- Hepatorenal syndrome and liver inflammation (Farzaneh and Moore, Prostaglandins Other Lipid Mediat, 72, 35 (2003)).

- Interstitial cystitis (Bouchelouche et al ., J Urol, 166, 1734 (2001)).

- Arteriosclerosis (Jala and Haribabu, Trends Immunol, 25, 315 (2004); Zhao et al ., Nat Med 10, 896 (2004)).

- Heart failure (Pfeifer et al ., Res Exp Med, 197, 177 (1997)).

- Hypertension (Stanke-Labesque et al ., Br J Pharmacol, 140, 186 (2003)).

- Cerebral ischemia (Yu et al ., Pharmacology, 73, 31 (2005); Zhang and Wei, Acta Pharmacol Sin, 26,435 (2005); Yu et al ., Brain Res, 1053, 116 (2005)).

- Migraine prophylaxis (Gazzaniga et al ., Headache, 27, 211 (1987); Sheftell et al ., Headache, 40, 158 (2000)).

- Colorectal cancer (Nielsen et al ., Adv Exp Med Biol., 525, 201 (2003); Ohd et al ., Gastroenterology, 124, 57 (2003).

From all this it follows that acting on leukotrienes and peptidoleukotrienes, either through inhibition of its synthesis or its receptors, represents a new pharmacological approach for the treatment of various inflammatory, anaphylactic or allergic states in which these molecules are involved. In recent years, the development of new and selective peptidoleukotriene antagonists has been a priority in this therapeutic field. There are currently various compounds in different stages of development with a mechanism of action of peptidoleukotriene antagonists LTD 4.

The present invention describes a series of imidazole derivatives (currently used as agents antihypertensives) leukotriene antagonists and / or peptidoleukotrienes, in particular peptidoleukotriene LTD 4 and / or the peptidoleukotriene LTC 4. These imidazole derivatives of general formula I, where R1, R2, R3 and R4 have the meaning listed below, are useful in treating various diseases and disorders that may present improvement by antagonism of leukotrienes and peptidoleukotrienes and that was unknown until now, such as the listed above, and are therefore useful for manufacture of drugs for their treatment. In particular, it is advantageous its use for the manufacture of medicines for the treatment of: bronchial asthma, chronic bronchitis, sinusitis eosinophilic, otitis media, chronic urticaria, nasal polyposis, Eosinophilic gastroenteritis, mastocytosis, pulmonary fibrosis idiopathic and / or cardiac anaphylaxis.

Explanation of the invention

The present invention relates to the use of imidazole derivatives of general formula (I)

2

in where

- R1 is a hydroxy radical; I rent (C1-C6) linear or branched; alkoxy (C1-C6); (C3-C8) cycloalkyl; cycloalkoxy (C3-C8); or carboxy, where said carboxy can be optionally substituted by an alkyl group (C1-C6) linear or branched;

- R2 is a carboxy group; alkoxycarbonyl (C1-C10); or a phenyl group, where said group phenyl can be optionally substituted in the ortho position by an acidic group;

- R3 is a hydrogen or halogen atom; a hydroxy radical; carboxy; (C1-C6) alkyl; hydroxyalkyl (C1-C6); alkoxy (C1-C6); (C3-C8) cycloalkyl; cycloalkoxy (C3-C8); Not me; alkylthio (C1-C6); cycloalkylthio (C3-C8); aryl; heteroaryl; aryloxy; heteroaryloxy; arylthio; or heteroarylthio, wherein said aryl, heteroaryl, aryloxy, heteroaryloxy, arylthio, or heteroarylthio may optionally be substituted by (C1-C4) alkyl, halogen, alkoxy (C1-C4), amino, alkylamino (C1-C4), carboxy or alkoxycarbonyl (C1-C6);

- R4 is a hydroxy radical; hydroxyalkyl (C1-C6); (C1-C6) alkoxy; (C3-C8) cycloalkyl; cycloalkoxy (C3-C8); Not me; (C1-C6) alkylamino; carboxy, where said carboxy may be optionally substituted giving rise to a physiologically acceptable ester; I rent (C1-C6); alkenyl (C2-C6), where said (C1-C6) alkyl or alkenyl (C2-C6) may be optionally substituted by carboxy, aryl, arylalkyl, heteroaryl, or arylthio, where said carboxy, aryl, arylalkyl, heteroaryl, or arylthio, in turn, can be optionally substituted by alkyl (C1-C4), carboxy or (C1-C4) alkoxy; aryl; heteroaryl; aryloxy; or heteroaryloxy, where said aryl, heteroaryl, aryloxy, or heteroaryloxy may optionally be substituted by (C1-C4) alkyl, halogen, alkoxy (C1-C4), amino, (C1-C4) alkylamino, carboxy or (C1-C6) alkoxycarbonyl; or

- R3 and R4 can form, together with the atoms of the imidazole ring to which they are attached, a bicyclic system where said bicyclic system is benzimidazole, imidazopyridine, imidazopyrimidine, thienoimidazole, imidazopyrazole, imidazopyridone or imidazopyridazinone;

or one of its salts or solvates physiologically acceptable, for the manufacture of a medicine for the treatment of a disorder that is mediated by a leukotriene or peptidoleukotriene.

Within the derivatives indicated above in formula I, preferred compounds of the invention are those in which:

R1 is an alkyl radical (C1-C4); cycloalkyl (C3-C6) or (C1-C4) alkoxy; more preferably R1 is a ethyl, propyl, cyclopropyl, butyl or ethoxy radical;

and / or R2 is a carboxy group; alkoxycarbonyl (C1-C6); or a phenyl group, wherein said phenyl is substituted in the ortho position of the ring by a character group acid selected from the group consisting of carboxy, tetrazole, alkylureidosulfonyl and arylcarboxamidosulfonyl; more preferably R2 is carboxy, 2-carboxyphenyl, 2-tetrazolylphenyl, 2- (propylureidosulfonyl) phenyl or 2- (phenylcarboxamidosulfonyl) phenyl;

and / or R3 is a hydrogen or halogen atom; (C1-C4) alkyl; cycloalkyl (C3-C6); 1-hydroxyalkyl (C1-C6); (C1-C4) alkylthio; carboxy; or (C1-C6) alkoxycarbonyl; more preferably R3 is hydrogen, chlorine, 1-hydroxy-1-methylethyl or methylthio;

and / or R4 is a hydroxyalkyl radical (C1-C6); carboxy, where said carboxy may be optionally substituted by 1- (ethoxycarbonyloxy) ethyl, 5-methyl-2-oxo-1,3-dioxol-4-ylmethyl or (C1-C4) alkyl; carboxyalkenyl, where said carboxyalkenyl can be optionally substituted by aryl, arylalkyl, or heteroaryl; or arylthioalkyl, where said arylthioalkyl may be optionally substituted by alkyl (C1-C4), carboxy or (C1-C4) alkoxy; more preferably R4 is hydroxymethyl, carboxy, 1- (ethoxycarbonyloxy) ethoxycarbonyl, 5-methyl-2-oxo-1,3-dioxol-4-ylmethyloxycarbonyl, 2-carboxy-3- (2-thienyl) -1-propenyl, 2-carboxy-3-phenyl-1-propenyl or 2-carboxyphenylthiomethyl.

Alternatively, R3 and R4 may, together with the imidazole ring to which they are attached, a system bicyclic.

Preferred bicyclic systems are benzimidazole, imidazopyridine, imidazopyrimidine, thienoimidazole, imidazopyrazole, imidazopyridone, or imidazopyridazinone. More preferably the bicyclic systems are 6- (hydroxymethyl) benzimidazole, 7-carboxybenzimidazole, 7- [1- (cyclohexyloxycarbonyloxy) ethoxycarbonyl] benzimidazole, 4-methyl-6- (1-methyl-1H-benzimidazol-2-yl) benzimidazole, 4-methyl-6- (5,6,7,8-tetrahydroimidazo [1,2-a] pyridin-2-yl) benzimidazole, 3H-imidazo
[4,5-b] pyridine, 5-carboxy-7-methyl-3H-imidazo [4,5-b] pyridine, 7-methyl-3H-imidazo [4,5-b] pyridine, 5,7-dimethyl -3H-imidazo [4,5-b] pyridine, 7- (hydroxymethyl) -3H-imidazo [4,5-b] pyridine, 5- (2-thienylmethyl) -4,5-dihydro-3H-imidazo [4 , 5-c] pyridin-4-one or 5- (2-methoxycarbonyl) benzyl-4,5-dihydro-3H-imidazo [4,5-c] pyridin-4-one.

Particularly preferred are compounds:

2-Butyl-4-chloro-5- (hydroxymethyl) -1- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] imidazole;

acid 3- [2-butyl-1- (4-carboxybenzyl) -1H-imidazol-5-yl] -2- (2-thienylmethyl) -2 (E) -propenoic;

(±) -2-ethoxy-1- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -1H-benzimidazole-7-carboxylic acid 1- (cyclohexyloxycar-
bonyloxy) ethyl ester;

acid 4 '- [4-Methyl-6- (1-methyl-1H-benzimidazol-2-yl) -2-propyl-1H-benzimidazol-1-ylmethyl] biphenyl-2-carboxylic;

The compounds of the present invention are antagonists of leukotrienes and peptidoleukotrienes and have a marked selectivity for LTD_ {4}, which makes them particularly useful as therapeutic agents in pathologies where a marked effect of LTD4 is observed, such as asthma, allergic rhinitis, chronic lung obstruction, etc.

The invention also has for its object the use of Imidazole derivatives of formula (I) for the manufacture of medicines intended for the treatment of pathologies where observes a marked effect of LTD 4, particularly for the manufacture of a drug for the treatment of respiratory diseases and for those in which it has been described a preponderant role of inflammatory processes as allergies, autoimmune diseases, cardiovascular diseases, cerebrovascular disease and cancer.

The compounds of general formula (I) can be synthesize according to the procedures described in various applications Patents including EP 0459136 (Takeda Pharm. Co., Ltd.), EP 0502314 (Dr. Karl Thomae GmbH), US 5089626 (Merck & Co., Inc.), EP 0503785 (Sankyo Co., Ltd.), EP 0403159 (GlaxoSmithKline plc).

Examples of pharmaceutical compositions that contain compounds of general formula (I) are described in Patent applications EP 0546358 (Takeda Pharm. Co., Ltd.), WO 2001001987 (AstraZeneca plc), WO 2005020971 (AstraZeneca plc).

Illustrative Examples of Compounds Covered in the present invention include the compounds that remain characterized with the data indicated in Tables 1 to 4.

TABLE 1

3

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TABLE 2

4

TABLE 3

5

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TABLE 4

6

The following pharmacological tests illustrate the invention.

Test: Inhibition of the binding of peptidoleukotriene LTD 4 to your receiver

The inhibitory activity of the binding of peptidoleukotriene LTD4 to its receptor for the exemplified products has been carried out following the method described by Martín et al . (Martin V., Sawyer N., Stocco R., Unett D., Lerner MR, Abramovitz M. and Funk CDMolecular cloning and functional characterization of murine cysteinyl-leukotriene 1 (CysLT (1)) receptors. Biochem. Pharmacol. 62: 1193-1200 (2001)).

The principle of the method is to evaluate the inhibition of specific ligand binding (labeled radioactively) of the receptor versus a concentration determined of the described compounds. For this they have been used CHO-K1 cells expressing the human receptor recombinant. As a specific ligand, [3H] has been used peptidoleukotriene D 4 (0.3 nM), and as a binding control no specific, a concentration of 300 nM of peptidoleukotriene D4. In the case of example 11 we have used different concentrations (1-10 µM) and in the case of Examples 1,2 and 12 a concentration of 10 µM. The studies have been done in duplicate.

Table 5 shows the results obtained in examples 1, 2, 11 and 12.

TABLE 5 Inhibition of peptidoleukotriene binding LTD_ {4} to your receiver

Example % Inhibition (10 µM) 1 7 2 3 eleven 100 12 38

In the case of example 11, the inhibition constant (Table 6).

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TABLE 6 Concentration that inhibits 50% of the binding of peptidoleukotriene LTD 4 to its receptor

Example IC_ {50} (µM) eleven 4.1

Forms of administration and dosage

The present invention furthermore relates to pharmaceutical compositions comprising, as active ingredient, at least one derivative of formula (I) or a salt or solvate pharmaceutically acceptable, and an excipient or diluent pharmaceutically acceptable.

Preferably the compositions are in a form suitable for oral, topical, inhalation, rectal, transdermal, nasal or parenteral administration. The pharmaceutically acceptable excipients or diluents which are mixed with the active compound (s) to form the compositions of this invention are well known per se and the actual excipients used depend on the method of administration of the compositions.

Compositions for Oral Administration they can take the form of tablets, capsules, lozenges or granules effervescent or liquid preparations such as elixirs, syrups or suspensions, all containing one or more compounds of the invention. Such preparations can be carried out by methods well known, for example mixing the derivatives of formula with pharmaceutically acceptable excipients or diluents.

The diluents that can be used in the Preparation of the compositions include liquid diluents and solids which are compatible with the active ingredients, together with coloring or sweetening agents, if desired. The Tablets or capsules may conveniently contain between 0.1 and 100 mg of active ingredient. Compounds can also be incorporated in pellets coated with natural polymers or synthetics known in the literature to produce controlled release characteristics or incorporate polymers into the tablet to produce the same characteristics.

Liquid compositions adapted for use oral, may be in the form of solutions, suspensions or aerosol sprays. Suspensions may include an insoluble or microencapsulated active compound of the invention in association with water and other acceptable solvents along with an agent thickener or sweetener.

Compositions for administration by inhalation can be in the form of solutions, suspensions or micronized powder, contained in a suitable inhaler.

Compositions for parenteral injection are prepared in the form of microemulsions or microsuspensions in water or in a fluid suitable for parenteral injection.

Claims (26)

1. Use of an imidazole derivative of formula general (I), 7 in where - R1 is a hydroxy radical; I rent (C1-C6) linear or branched; alkoxy (C1-C6); (C3-C8) cycloalkyl; cycloalkoxy (C3-C8); or carboxy, where said carboxy can be optionally substituted by an alkyl group (C1-C6) linear or branched; - R2 is a carboxy group; alkoxycarbonyl (C1-C10); or a phenyl group, where said group phenyl may be optionally substituted in the ortho position by a acid group; - R3 is a hydrogen or halogen atom; a hydroxy radical; carboxy; (C1-C6) alkyl; hydroxyalkyl (C1-C6); alkoxy (C1-C6); (C3-C8) cycloalkyl; cycloalkoxy (C3-C8); Not me; alkylthio (C1-C6); cycloalkylthio (C3-C8); aryl; heteroaryl; aryloxy; heteroaryloxy; arylthio; or heteroarylthio, wherein said aryl, heteroaryl, aryloxy, heteroaryloxy, arylthio, or heteroarylthio may optionally be substituted by (C1-C4) alkyl, halogen, alkoxy (C1-C4), amino, alkylamino (C1-C4), carboxy or alkoxycarbonyl (C1-C6); - R4 is a hydroxy radical; hydroxyalkyl (C1-C6); (C1-C6) alkoxy; (C3-C8) cycloalkyl; cycloalkoxy (C3-C8); Not me; (C1-C6) alkylamino; carboxy, where said carboxy may be optionally substituted giving rise to a physiologically acceptable ester; I rent (C1-C6); alkenyl (C2-C6), where said (C1-C6) alkyl or alkenyl (C2-C6) may be optionally substituted by carboxy, aryl, arylalkyl, heteroaryl, or arylthio, where said carboxy, aryl, arylalkyl, heteroaryl, or arylthio, in turn, can be optionally substituted by alkyl (C1-C4), carboxy or (C1-C4) alkoxy; aryl; heteroaryl; aryloxy; or heteroaryloxy, where said, aryl, heteroaryl, aryloxy, or heteroaryloxy may optionally be substituted by (C1-C4) alkyl, halogen, alkoxy (C1-C4), amino, (C1-C4) alkylamino, carboxy or (C1-C6) alkoxycarbonyl; or - R3 and R4 can form, together with the atoms of the imidazole ring to which they are attached, a bicyclic system where said bicyclic system is benzimidazole, imidazopyridine, imidazopyrimidine, thienoimidazole, imidazopyrazole, imidazopyridone or imidazopyridazinone; or one of its salts or solvates physiologically acceptable, for the manufacture of a medicine for the treatment of a disorder that is mediated by a leukotriene or peptidoleukotriene. 2. Use according to claim 1, characterized in that R1 is a (C1-C4) alkyl radical; (C3-C6) cycloalkyl or (C1-C4) alkoxy. 3. Use according to claim 2, characterized in that R1 is an ethyl, propyl, cyclopropyl, butyl or ethoxy radical. 4. Use according to any one of claims 1 to 3, characterized in that R2 is a carboxy group; (C1-C6) alkoxycarbonyl; or a phenyl group, wherein said phenyl is substituted in the ortho position of the ring by an acidic group selected from the group consisting of carboxy, tetrazole, alkylureidosulfonyl and arylcarboxamidosulfonyl. 5. Use according to claim 4, characterized in that R2 is carboxy, 2-carboxyphenyl, 2-tetrazolylphenyl, 2- (propyl-
reidosulfonyl) phenyl or 2- (phenylcarboxamidosulfonyl) phenyl. 6. Use according to any one of claims 1 to 5, characterized in that R3 is a hydrogen or halogen atom; (C1-C4) alkyl; (C3-C6) cycloalkyl; 1-hydroxyalkyl (C1-C6); (C1-C4) alkylthio; carboxy; or (C1-C6) alkoxycarbonyl. 7. Use according to claim 6, characterized in that R3 is hydrogen, chlorine, 1-hydroxy-1-methylethyl or methylthio. 8. Use according to any one of claims 1 to 7, characterized in that R4 is a hydroxyalkyl radical (C1-C6); carboxy, wherein said carboxy may be optionally substituted by 1- (ethoxycarbonyloxy) ethyl, 5-methyl-2-oxo-1,3-dioxol-4-ylmethyl or (C1-C4) alkyl; carboxyalkenyl, where said carboxyalkenyl may be optionally substituted by aryl, arylalkyl, or heteroaryl; or arylthioalkyl, wherein said arylthioalkyl may be optionally substituted by (C1-C4) alkyl, carboxy or (C1-C4) alkoxy. 9. Use according to claim 8, characterized in that R4 is hydroxymethyl, carboxy, 1- (ethoxycarbonyloxy) ethoxycarbonyl, 5-methyl-2-oxo-1,3-dioxol-4-ylmethyloxycarbonyl, 2-carboxy-3- (2- thienyl) -1-propenyl, 2-carboxy-3-phenyl-1-propenyl or 2-carboxyphenylthiomethyl. Use according to any of claims 1 to 5, characterized in that said bicyclic system is 6- (hydroxymethyl) benzimidazole, 7-carboxybenzimidazole, 7- [1- (cyclohexyloxycarbonyloxy) ethoxycarbonyl] benzimidazole, 4-methyl-6- (1- methyl-1H-benzimidazol-2-yl) benzimidazole, 4-methyl-6- (5,6,7,8-tetrahydroimidazo [1,2-a] pyridin-2-yl) benzimidazole, 3H-imidazo [4,5 -b] pyridine, 5-carboxy-7-methyl-3H-imidazo [4,5-b] pyridine, 7-methyl-3H-imidazo [4,5-b] pyridine, 5,7-dimethyl-3H-imidazo [4,5-b] pyridine, 7- (hydroxymethyl) -3H-imidazo [4,5-b] pyridine, 5- (2-thienylmethyl) -4,5-dihydro-3H-imidazo [4,5-c ] pyridin-4-one or 5- (2-methoxycarbonyl) benzyl-4,5-dihydro-3H-imidazo [4,5-c] pyridin-4-one. 11. Use according to claim 1, characterized in that said imidazole derivative is 2-Butyl-4-chloro-5- (hydroxy-
methyl) -1- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] imidazole. Use according to claim 1, characterized in that said imidazole derivative is 3- [2-butyl-1- (4-carboxybenzyl) -1H-imidazol-5-yl] -2- (2-thienylmethyl) -2 ( E) -propenoic. 13. Use according to claim 1, characterized in that said imidazole derivative is (±) -2-ethoxy-1- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -1H-benzimidazole acid -7-carboxylic 1- (cyclohexyloxycarbonyloxy) ethyl ester. 14. Use according to claim 1, characterized in that said imidazole derivative is 4 '- [4-Methyl-6- (1-methyl-1H-benzimidazol-2-yl) -2-propyl-1H-benzimidazol-1- acid. ylmethyl] biphenyl-2-carboxylic. Use according to any one of claims 1 to 14, characterized in that it is for the manufacture of a medicament for the treatment of a disorder that is mediated by peptidoleukotriene LTD 4. Use according to any one of claims 1 to 15, characterized in that it is for the manufacture of a medicament for the treatment of a disorder that is mediated by the LTC 4 peptidoleukotriene. 17. Use according to any of claims 1 to 16, characterized in that it is for the manufacture of a drug for the treatment of bronchial asthma. 18. Use according to any of claims 1 to 16, characterized in that it is for the manufacture of a drug for the treatment of chronic bronchitis. 19. Use according to any of claims 1 to 16, characterized in that it is for the manufacture of a drug for the treatment of eosinophilic sinusitis. 20. Use according to any of claims 1 to 16, characterized in that it is for the manufacture of a medicine for the treatment of otitis media. 21. Use according to any of claims 1 to 16, characterized in that it is for the manufacture of a drug for the treatment of chronic urticaria. 22. Use according to any of claims 1 to 16, characterized in that it is for the manufacture of a drug for the treatment of nasal polyposis. 23. Use according to any of claims 1 to 16, characterized in that it is for the manufacture of a drug for the treatment of eosinophilic gastroenteritis. 24. Use according to any of claims 1 to 16, characterized in that it is for the manufacture of a drug for the treatment of mastocytosis. 25. Use according to any of claims 1 to 16, characterized in that it is for the manufacture of a drug for the treatment of idiopathic pulmonary fibrosis. 26. Use according to any of claims 1 to 16, characterized in that it is for the manufacture of a drug for the treatment of cardiac anaphylaxis.