ES2246742A1 - Use of a derivative of imidazole - Google Patents

Use of a derivative of imidazole

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ES2246742A1
ES2246742A1 ES200502163A ES200502163A ES2246742A1 ES 2246742 A1 ES2246742 A1 ES 2246742A1 ES 200502163 A ES200502163 A ES 200502163A ES 200502163 A ES200502163 A ES 200502163A ES 2246742 A1 ES2246742 A1 ES 2246742A1
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carboxy
use according
alkyl
alkoxy
treatment
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ES2246742B1 (en
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Josep Prous Blancafort
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Prous Science SA
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/41641,3-Diazoles
    • A61K31/41841,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/41641,3-Diazoles
    • A61K31/41781,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • A61P11/06Antiasthmatics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00Drugs for dermatological disorders

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pulmonology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Use of a derivative of imidazole. Use of a derivative of imidazole having the formula (I),wherein - Rl is a radical hydroxy linear or branched alkyl (Cl-C6) alkoxy (C1-C6) cycloalkyl (C3-C8) cycloalkoxy (C3-C8) or carboxy, where optionally said carboxy can be replaced by a linear or branched alkyl group (C1-C6) - R2 is a carboxy group alcoxycarbonyl (Cl-ClO) or a phenyl group, where optionally said phenyl group can be replaced in the ortho position by an acid group R3 is a hydrogen or halogen atom a radical hydroxy carboxy alkyl (C1-C6) hydroxyalkyl (C1-C6) alkoxy (C1-C6) cycloalkyl (C3-C8) cycloalkoxy (C3-C8) amino alkylthio (Cl-C6) cycloalkylthio (C3-C8) aryl heteroaryl aryloxy heteroaryloxy arylthio or heteroarylthio, where optionally said aryl, heteroaryl, aryloxy, heteroaryloxy, arylthio or heteroarylthio can be replaced by alkyl (C1-C4), halogen, alkoxy (C1-C4), amino, alkylamino (C1-C4), carboxy or alkoxycarbonyl (C1-C6) R4 is a radical hydroxy hydroxyalkyl (C1-C6) alkoxy (C1-C6) cycloalkyl (C3-C8) cycloalkoxy (C3-C8) amino alkylamino (C1-C6) carboxy, where optionally said carboxy can be replaced leading to a physiologically acceptable ester,- alkyl (C1-C6) alkenyl (C2-C6), where optionally said alkyl (C1-C6) or alkenyl (C2-C6) can be replaced by carboxy, aryl, arylalkyl, heteroaryl, or arylthio, where optionally said carboxy, aryl, arylalkyl, heteroaryl, or arylthio, in turn, can be replaced by alkyl (C1-C4), carboxy or alkoxy (C1-C4),- aryl heteroaryl aryloxy or heteroaryloxy, where optionally said aryl, heteroaryl, aryloxy or heteroaryloxy can be replaced by alkyl (C1-C4), halogen, alkoxy (C1-C4) , amino, alkylamino (C1-C4), carboxy or alkoxycarbonyl (C1-C6)- or R3 and R4 can make up, together with the atoms of the imidazole ring to which they are attached, a bicyclical system where said bicyclical system is benzimidazole, imidazopyridine, imidazopyrimidine, thienoimidazole, imidazopyrazole, imidazopyridone or imidazopyridazinone,- or one of the sales or physiologically acceptable solvates thereof, to produce a medicine for the treatment of a disorder that is involving a leukotriene or peptidoleukotriene.

Description

Uso de un derivado de imidazol.Use of an imidazole derivative.

Sector de la técnica al que se refiere la invenciónTechnical sector to which the invention relates

La presente invención se refiere al empleo de derivados de imidazol de fórmula general (I),The present invention relates to the use of imidazole derivatives of general formula (I),

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11

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así como de sus sales o solvatos fisiológicamente aceptables, en la elaboración de medicamentos, útiles en terapéutica humana, para el tratamiento de los trastornos que vienen mediados por leucotrienos o péptidoleucotrienos, por ejemplo el LTD_{4}, como son entre otros ciertos trastornos del sistema respiratorio, cardiovascular, digestivo, genitourinario, nervioso, osteomuscular, afecciones cutáneas o algunos tipos de cáncer.as well as its salts or solvates physiologically acceptable, in the elaboration of medicines, useful in human therapy, for the treatment of disorders that are mediated by leukotrienes or peptidoleukotrienes, for example LTD 4, such as certain disorders of the system among others respiratory, cardiovascular, digestive, genitourinary, nervous, musculoskeletal, skin conditions or some types of cancer.

Estado de la técnica de la invenciónState of the art of the invention

El uso de corticosteroides inhalados en el tratamiento de procesos asmáticos presenta, a pesar de su eficacia, algunos efectos indeseados así como toxicidad, sobre todos en niños. Además, en un buen número de pacientes, no se consigue el control terapéutico necesario deseado, por lo que es importante encontrar nuevos agentes antiasmáticos que presenten menos efectos secundarios. Una de las nuevas aproximaciones terapéuticas es el uso de antagonistas de los péptidoleucotrienos, que además de su potencial broncodilatador también presentan actividad antiinflamatoria.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.

La mayor parte de leucotrienos derivan del ácido araquidónico, un ácido graso que se libera del fosfolipido que lo contiene por acción de la fosfolipasa A_{2}. El ácido araquidónico se metaboliza a su vez principalmente por dos sistemas enzimáticos diferentes. Uno, a través de la ciclooxigenasa, produce tromboxano y prostaglandinas, mediadores de la inflamación, pero que también participan en funciones como la contracción muscular, transporte del calcio, regulación hormonal y control del crecimiento celular. El otro, a través de las lipoxigenasas, produce ácidos hidroxieicosateraenoicos y leucotrienos, siendo los más importantes de éstos últimos el leucotrieno LTB_{4} y los péptidoleucotrienos LTC_{4}, LTD_{4} y LTE_{4} (Higgs et al. Annals of Clinical Research 16, 287 (1984)). Todos ellos también participan de la reacción inflamatoria estando implicados de forma considerable en las reacciones de hipersensibilidad inmediata (Bayley y Casey, Ann. Rep. Med. Chem., 17, 203 (1982)).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)).

El LTD_{4} es un potente broncoconstrictor, al tiempo que induce contracción de la musculatura lisa, depresión miocardial, incremento de la permeabilidad vascular y de la producción de mucosidad (Marom et al., Am. Rev. Resp. Dis., 126, 449 (1982)), por lo que está directamente implicado en la patogenia de: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:

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

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

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

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

Además, tanto LTC_{4} como LTD_{4} inducen contracción exagerada en el tejido cardíaco con lo que se ha sugerido su implicación en situaciones de anafilaxis cardíaca (Marone et al., Int Arch Allergy Immunol, 107,72 (1995), shock endotóxico (Cinar et al., Eur J Pharmacol, 350, 223 (1998), o edema cerebral (Di Gennaro et al., FASEB J, 18, 842 (2004)).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)).

Asimismo se ha demostrado de manera convincente la importancia del leucotriemo LTD_{4} en numerosas patologías relacionadas con procesos inflamatorios. Existe abundante evidencia experimental y clínica que describe el importante papel que los fármacos bloqueadores del receptor del LTD_{4} pueden jugar como arma terapéutica en el tratamiento de estas condiciones: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:

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

- Sinusitis eosinofílica (Steinke y Borish, Curr Allergy Asthma Rep, 4, 217 (2004); Corrigan et al., J Allergy Clin Immunol, 115, 316 (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)).- Otitis media (Tada et al ., Auris Nasus Larynx, 29, 127 (2002)).

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

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

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

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

- Gastroenteritis eosinofílica (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)).- 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)).

- Síndrome del intestino irritable (Fee, Chest, 122, 1497 (2002)).- Irritable bowel syndrome (Fee, Chest, 122, 1497 (2002)).

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

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

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

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

- Síndrome hepatorenal e inflamación hepática (Farzaneh y Moore, Prostaglandins Other Lipid Mediat, 72, 35 (2003)).- Hepatorenal syndrome and liver inflammation (Farzaneh and Moore, Prostaglandins Other Lipid Mediat, 72, 35 (2003)).

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

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

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

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

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

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

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

De todo ello se desprende que la actuación sobre los leucotrienos y péptidoleucotrienos, bien sea través la inhibición de su síntesis o bien sobre sus receptores, representa una nueva aproximación farmacológica para el tratamiento de diversos estados inflamatorios, anafilácticos o alérgicos en que estas moléculas estén implicadas. En los últimos años, el desarrollo de nuevos y selectivos antagonistas de los péptidoleucotrienos ha sido una prioridad en este campo terapéutico. Existen actualmente diversos compuestos en diferentes fases de desarrollo con un mecanismo de acción de antagonistas del péptidoleucotrieno LTD_{4}.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.

La presente invención describe una serie de derivados de imidazol (actualmente usados como agentes antihipertensivos) antagonistas de leucotrienos y/o de péptidoleucotrienos, en particular del péptidoleucotrieno LTD_{4} y/o del péptidoleucotrieno LTC_{4}. Estos derivados de imidazol de fórmula general I, donde R1, R2, R3 y R4 tienen el significado que se indica a continuación, son de utilidad en el tratamiento de diversas enfermedades y alteraciones susceptibles de presentar mejoría mediante antagonismo de leucotrienos y péptidoleucotrienos y que era desconocida hasta el momento, como por ejemplo las indicadas anteriormente, y, por lo tanto, son útiles para la fabricación de medicamentos para su tratamiento. En particular, es ventajoso su uso para la fabricación de medicamentos para el tratamiento de: asma bronquial, bronquitis crónica, sinusitis eosinofílica, otitis media, urticaria crónica, poliposis nasal, gastroenteritis eosinofílica, mastocitosis, fibrosis pulmonar idiopática y/o anafilaxis cardíaca.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.

Explicación de la invenciónExplanation of the invention

La presente invención se refiere al empleo de derivados de imidazol de fórmula general (I)The present invention relates to the use of imidazole derivatives of general formula (I)

22

en dondein where

- R1 es un radical hidroxi; alquilo (C1-C6) lineal o ramificado; alcoxi (C1-C6); cicloalquilo (C3-C8); cicloalcoxi (C3-C8); o carboxi, donde dicho carboxi puede ser opcionalmente substituido por un grupo alquilo (C1-C6) lineal o ramificado;- 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 es un grupo carboxi; alcoxicarbonil (C1-C10); o un grupo fenilo, donde dicho grupo fenilo puede estar opcionalmente substituido en posición orto por un grupo de carácter ácido;- 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 es un átomo de hidrógeno o de halógeno; un radical hidroxi; carboxi; alquilo (C1-C6); hidroxialquilo (C1-C6); alcoxi (C1-C6); cicloalquilo (C3-C8); cicloalcoxi (C3-C8); amino; alquiltio (C1-C6); cicloalquiltio (C3-C8); arilo; heteroarilo; ariloxi; heteroariloxi; ariltio; o heteroariltio, donde dichos arilo, heteroarilo, ariloxi, heteroariloxi, ariltio o heteroariltio pueden estar opcionalmente substituidos por alquilo (C1-C4), halógeno, alcoxi (C1-C4), amino, alquilamino (C1-C4), carboxi o alcoxicarbonil (C1-C6);- 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 es un radical hidroxi; hidroxialquil (C1-C6); alcoxi (C1-C6); cicloalquilo (C3-C8); cicloalcoxi (C3-C8); amino; alquilamino (C1-C6); carboxi, donde dicho carboxi puede estar opcionalmente sustituido dando lugar a un éster fisiológicamente aceptable; alquilo (C1-C6); alquenilo (C2-C6), donde dichos alquilo (C1-C6) o alquenilo (C2-C6) pueden estar opcionalmente sustituidos por carboxi, aril, arilalquil, heteroaril, o ariltio, donde dichos carboxi, aril, arilalquil, heteroaril, o ariltio, a su vez, pueden estar opcionalmente sustituidos por alquilo (C1-C4), carboxi o alcoxi (C1-C4); arilo; heteroarilo; ariloxi; o heteroariloxi, donde dichos arilo, heteroarilo, ariloxi o heteroariloxi pueden estar opcionalmente sustituidos por alquilo (C1-C4), halógeno, alcoxi (C1-C4), amino, alquilamino (C1-C4), carboxi o alcoxicarbonil (C1-C6); ó- 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 y R4 pueden formar, junto con los átomos del anillo de imidazol al que están unidos, un sistema bicíclico donde dicho sistema bicíclico es bencimidazol, imidazopiridina, imidazopirimidina, tienoimidazol, imidazopirazol, imidazopiridona o imidazopiridazinona;- 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;

o una de sus sales o solvatos fisiológicamente aceptables, para la fabricación de un medicamento para el tratamiento de un trastorno que viene mediado por un leucotrieno o péptidoleucotrieno.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.

Dentro de los derivados indicados anteriormente en la fórmula I son compuestos preferidos de la invención aquellos en los que:Within the derivatives indicated above in formula I, preferred compounds of the invention are those in which:

R1 es un radical alquilo (C1-C4); cicloalquilo (C3-C6) o alcoxi (C1-C4); más preferiblemente R1 es un radical etilo, propilo, ciclopropilo, butilo o etoxi;R1 is a (C1-C4) alkyl radical; cycloalkyl (C3-C6) or alkoxy (C1-C4); more preferably R1 is a radical ethyl, propyl, cyclopropyl, butyl, or ethoxy;

y/o R2 es un grupo carboxi; alcoxicarbonil (C1-C6); o un grupo fenilo, donde dicho fenilo está substituido en la posición orto del anillo por un grupo de carácter ácido que se selecciona del grupo formado por carboxi, tetrazol, alquilureidosulfonil y arilcarboxamidosulfonil; más preferiblemente R2 es carboxi, 2-carboxifenil, 2-tetrazolilfenil, 2-(propilureidosulfonil)fenil o 2-(fenilcarboxamidosulfonil)fenil;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;

y/o R3 es un átomo de hidrógeno o de halógeno; alquilo (C1-C4); cicloalquilo (C3-C6); 1-hidroxialquilo (C1-C6); alquiltio (C1-C4); carboxi; o alcoxicarbonil (C1-C6); más preferiblemente R3 es hidrógeno, cloro, 1-hidroxi-1-metiletil o metiltio;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;

y/o R4 es un radical hidroxialquil (C1-C6); carboxi, donde dicho carboxi puede estar opcionalmente sustituido por 1-(etoxicarboniloxi)etil, 5-metil-2-oxo-1,3-dioxol-4-ilmetil o alquilo (C1-C4); carboxialquenil, donde dicho carboxialquenil puede estar opcionalmente sustituido por aril, arilalquil, o heteroaril; o ariltioalquil, donde dicho ariltioalquil puede estar opcionalmente sustituidos por alquilo (C1-C4), carboxi o alcoxi (C1-C4); más preferiblemente R4 es hidroximetil, carboxi, 1-(etoxicarboniloxi)etoxicarbonil, 5-metil-2-oxo-1,3-dioxol-4-ilmetiloxicarbonil, 2-carboxi-3-(2-tienil)-1-propenil, 2-carboxi-3-fenil-1-propenil o 2-carboxifeniltiometil.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.

Alternativamente, R3 y R4 pueden formar, junto con el anillo de imidazol al que están unidos, un sistema biciclico.Alternatively, R3 and R4 may, together with the imidazole ring to which they are attached, a system bicyclic.

Sistemas biciclicos preferidos son bencimidazol, imidazopiridina, imidazopirimidina, tienoimidazol, imidazopirazol, imidazopiridona o imidazopiridazinona. Más preferiblemente los sistemas bicíclicos son 6-(hidroximetil)bencimidazol, 7-carboxibencimidazol,7-[1-(ciclohexiloxicarboniloxi) etoxicarbonil] bencimidazol, 4-metil-6-(1-metil-1H-bencimidazol-2-il)bencimidazol, 4-metil-6-(5,6,7,8-tetrahidroimidazo[1,2-a]piridin-2-il)bencimidazol, 3H-imidazo
[4,5-b]piridina, 5-carboxi-7-metil-3H-imidazo[4,5-b]piridina, 7-metil-3H-imidazo[4,5-b]piridina, 5,7-dimetil-3H-imidazo[4,5-b]piridina, 7-(hidroximetil)-3H-imidazo[4,5-b]piridina, 5-(2-tienilmetil)-4,5-dihidro-3H-imidazo[4,5-c]piridin-4-ona o 5-(2-metoxicarbonil)bencil-4,5-dihidro-3H-imidazo[4,5-c]piridin-4-ona.
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.

Son particularmente preferentes los compuestos:Particularly preferred are compounds:

2-Butil-4-cloro-5-(hidroximetil)-1-[2'-(1H-tetrazol-5-il)bifenil-4-ilmetil]imidazol;2-Butyl-4-chloro-5- (hydroxymethyl) -1- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] imidazole;

ácido 3-[2-butil-1-(4-carboxibencil)-1H-imidazol-5-il]-2-(2-tienilmetil)-2(E)-propenoico;acid 3- [2-butyl-1- (4-carboxybenzyl) -1H-imidazol-5-yl] -2- (2-thienylmethyl) -2 (E) -propenoic;

ácido (\pm)-2-etoxi-1-[2'-(1H-tetrazol-5-il)bifenil-4-ilmetil]-1H-benzimidazol-7-carboxílico 1-(ciclohexiloxicar-
boniloxi)etil éster;
(±) -2-ethoxy-1- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -1H-benzimidazole-7-carboxylic acid 1- (cyclohexyloxycar-
bonyloxy) ethyl ester;

ácido 4'-[4-Metil-6-(1-metil-1H-bencimidazol-2-il)-2-propil-1H-bencimidazol-1-ilmetil]bifenil-2-carboxílico;acid 4 '- [4-Methyl-6- (1-methyl-1H-benzimidazol-2-yl) -2-propyl-1H-benzimidazol-1-ylmethyl] biphenyl-2-carboxylic;

Los compuestos de la presente invención son antagonistas de leucotrienos y péptidoleucotrienos y presentan una marcada selectividad por el LTD_{4}, lo que les hace particularmente útiles como agentes terapéuticos en patologías donde se observa un marcado efecto de LTD_{4}, como por ejemplo asma, rinitis alérgica, obstrucción pulmonar crónica, etc.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.

La invención también tiene por objeto el uso de derivados de imidazol de fórmula (I) para la manufactura de medicamentos destinados al tratamiento de patologías donde se observa un marcado efecto del LTD_{4}, en particular para la manufactura de un medicamento para el tratamiento de las enfermedades respiratorias y para aquellas en las que se ha descrito un papel preponderante de los procesos inflamatorios como alergias, enfermedades autoinmunes, enfermedades cardiovasculares, cerebrovasculares y cáncer.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.

Los compuestos de fórmula general (I) se pueden sintetizar según los procedimientos descritos en varias solicitudes de patentes, entre las que figuran 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).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).

Ejemplos de composiciones farmacéuticas que contienen compuestos de fórmula general (I) se describen en las solicitudes de patentes EP 0546358 (Takeda Pharm. Co., Ltd.), WO 2001001987 (AstraZeneca plc), WO 2005020971 (AstraZeneca 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).

Ejemplos ilustrativos de compuestos comprendidos en la presente invención incluyen los compuestos que queda caracterizados con los datos indicados en las Tablas 1 a 4.Illustrative Examples of Compounds Covered in the present invention include the compounds that remain characterized with the data indicated in Tables 1 to 4.

TABLA 1TABLE 1

33

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TABLA 2TABLE 2

44

TABLA 3TABLE 3

55

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TABLA 4TABLE 4

66

Los siguientes ensayos farmacológicos ilustran la invención.The following pharmacological tests illustrate the invention.

Test: Inhibición del la unión del péptidoleucotrieno LTD_{4} a su receptorTest: Inhibition of the binding of peptidoleukotriene LTD 4 to your receiver

La actividad inhibitoria de la unión del péptidoleucotrieno LTD_{4} a su receptor para los productos ejemplificados, se ha llevado a cabo siguiendo el método descrito por Martín et al. (Martin V., Sawyer N., Stocco R., Unett D., Lerner M.R., Abramovitz M. and Funk C.D.Molecular cloning and functional characterization of murine cysteinyl-leukotriene 1 (CysLT(1)) receptors. Biochem. Pharmacol. 62: 1193-1200 (2001)).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)).

El principio del método consiste en evaluar la inhibición de la unión del ligando específico (marcado radioactivamente) del receptor frente a una concentración determinada de los compuestos descritos. Para ello se han usado células CHO-K1 que expresan el receptor humano recombinante. Como ligando específico se ha usado el [3H] péptidoleucotrieno D_{4} (0.3 nM), y como control de la unión no específica se ha utilizado una concentración de 300 nM de péptidoleucotrieno D_{4}. En el caso del ejemplo 11 se han utilizado distintas concentraciones (1-10 \muM) y en el caso de los ejemplos 1,2 y 12 una concentración de 10 \muM. Los estudios se han realizado por duplicado.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.

En la Tabla 5 se muestran los resultados obtenidos en los ejemplos 1, 2, 11 y 12.Table 5 shows the results obtained in examples 1, 2, 11 and 12.

TABLA 5TABLE 5 Inhibición de la unión del péptidoleucotrieno LTD_{4} a su receptorInhibition of peptidoleukotriene binding LTD_ {4} to your receiver

Ejemplo Example % Inhibición (10 \muM)% Inhibition (10 µM) 11 77 22 33 11eleven 100100 1212 3838

En el caso del ejemplo 11 se ha calculado la constante de inhibición (Tabla 6).In the case of example 11, the inhibition constant (Table 6).

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TABLA 6TABLE 6 Concentración que inhibe el 50% de la unión del péptidoleucotrieno LTD_{4} a su receptorConcentration that inhibits 50% of the binding of peptidoleukotriene LTD 4 to its receptor

EjemploExample IC_{50} (\muM)IC_ {50} (µM) 11eleven 4.14.1

Formas de administración y dosisForms of administration and dosage

La presente invención se refiere, además, a composiciones farmacéuticas que comprenden, como ingrediente activo, al menos un derivado de fórmula (I) o una sal o solvato farmacéuticamente aceptable, y un excipiente o diluyente farmacéuticamente aceptable.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.

Preferentemente las composiciones están en forma apropiada para la administración oral, tópica, inhalación, rectal, transdermal, nasal o parenteral. Los excipientes o diluyentes farmacéuticamente aceptables los cuales se mezclan con el compuesto o compuestos activos para formar las composiciones de esta invención, son bien conocidos per se y los excipientes reales utilizados dependen del método de administración de las composiciones.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.

Las composiciones para administración oral pueden tomar la forma de comprimidos, cápsulas, grageas o gránulos efervescentes o preparaciones líquidas como elixires, jarabes o suspensiones, conteniendo todas ellas uno o más compuestos de la invención. Tales preparaciones se pueden llevar a cabo por métodos bien conocidos, por ejemplo mezclando los derivados de fórmula con los excipientes o diluyentes farmacéuticamente aceptables.Compositions for oral administration 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.

Los diluyentes que pueden utilizarse en la preparación de las composiciones incluyen diluyentes líquidos y sólidos los cuales son compatibles con los ingredientes activos, junto con agentes colorantes o edulcorantes, si se desea. Los comprimidos o cápsulas pueden contener convenientemente entre 0,1 y 100 mg de ingrediente activo. Los compuestos también pueden ser incorporados en pellets recubiertos con polímeros naturales o sintéticos conocidos en la bibliografía para producir características de liberación controlada o incorporar polímeros en el comprimido para producir las mismas características.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.

Las composiciones líquidas adaptadas para el uso oral, pueden estar en forma de soluciones, suspensiones o aerosoles. Las suspensiones pueden incluir una forma insoluble o microencapsulada del compuesto activo de la invención en asociación con agua y otros disolventes aceptables junto con un agente espesante o edulcorante.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.

Las composiciones para administración por inhalación pueden estar en forma de soluciones, suspensiones o polvo micronizado, contenidas en un inhalador apropiado.Compositions for administration by inhalation can be in the form of solutions, suspensions or micronized powder, contained in a suitable inhaler.

Las composiciones para inyección parenteral se preparan en la forma de microemulsiones o microsuspensiones en agua o en un fluido apropiado para inyección parenteral.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. Uso de un derivado de imidazol de fórmula general (I),1. Use of an imidazole derivative of formula general (I), 77 en dondein where - R1 es un radical hidroxi; alquilo (C1-C6) lineal o ramificado; alcoxi (C1-C6); cicloalquilo (C3-C8); cicloalcoxi (C3-C8); o carboxi, donde dicho carboxi puede ser opcionalmente substituido por un grupo alquilo (C1-C6) lineal o ramificado;- 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 es un grupo carboxi; alcoxicarbonil (C1-C10); o un grupo fenilo, donde dicho grupo fenilo puede estar opcionalmente substituido en posición orto por un grupo de carácter ácido;- 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 es un átomo de hidrógeno o de halógeno; un radical hidroxi; carboxi; alquilo (C1-C6); hidroxialquilo (C1-C6); alcoxi (C1-C6); cicloalquilo (C3-C8); cicloalcoxi (C3-C8); amino; alquiltio (C1-C6); cicloalquiltio (C3-C8); arilo; heteroarilo; ariloxi; heteroariloxi; ariltio; o heteroariltio, donde dichos arilo, heteroarilo, ariloxi, heteroariloxi, ariltio o heteroariltio pueden estar opcionalmente substituidos por alquilo (C1-C4), halógeno, alcoxi (C1-C4), amino, alquilamino (C1-C4), carboxi o alcoxicarbonil (C1-C6);- 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 es un radical hidroxi; hidroxialquil (C1-C6); alcoxi (C1-C6); cicloalquilo (C3-C8); cicloalcoxi (C3-C8); amino; alquilamino (C1-C6); carboxi, donde dicho carboxi puede estar opcionalmente sustituido dando lugar a un éster fisiológicamente aceptable; alquilo (C1-C6); alquenilo (C2-C6), donde dichos alquilo (C1-C6) o alquenilo (C2-C6) pueden estar opcionalmente sustituidos por carboxi, aril, arilalquil, heteroaril, o ariltio, donde dichos carboxi, aril, arilalquil, heteroaril, o ariltio, a su vez, pueden estar opcionalmente sustituidos por alquilo (C1-C4), carboxi o alcoxi (C1-C4); arilo; heteroarilo; ariloxi; o heteroariloxi, donde dichos, arilo, heteroarilo, ariloxi o heteroariloxi pueden estar opcionalmente sustituidos por alquilo (C1-C4), halógeno, alcoxi (C1-C4), amino, alquilamino (C1-C4), carboxi o alcoxicarbonil (C1-C6); ó- 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 y R4 pueden formar, junto con los átomos del anillo de imidazol al que están unidos, un sistema biciclico donde dicho sistema biciclico es bencimidazol, imidazopiridina, imidazopirimidina, tienoimidazol, imidazopirazol, imidazopiridona o imidazopiridazinona;- 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; o una de sus sales o solvatos fisiológicamente aceptables, para la fabricación de un medicamento para el tratamiento de un trastorno que viene mediado por un leucotrieno o péptidoleucotrieno.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. Uso según la reivindicación 1, caracterizado porque R1 es un radical alquilo (C1-C4); cicloalquilo (C3-C6) o alcoxi (C1-C4).2. Use according to claim 1, characterized in that R1 is a (C1-C4) alkyl radical; (C3-C6) cycloalkyl or (C1-C4) alkoxy. 3. Uso según la reivindicación 2, caracterizado porque R1 es un radical etilo, propilo, ciclopropilo, butilo o etoxi.3. Use according to claim 2, characterized in that R1 is an ethyl, propyl, cyclopropyl, butyl or ethoxy radical. 4. Uso según cualquiera de las reivindicaciones 1 a 3, caracterizado porque R2 es un grupo carboxi; alcoxicarbonil (C1-C6); o un grupo fenilo, donde dicho fenilo está substituido en la posición orto del anillo por un grupo de carácter ácido que se selecciona del grupo formado por carboxi, tetrazol, alquilureidosulfonil y arilcarboxamidosulfonil.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. Uso según la reivindicación 4, caracterizado porque R2 es carboxi, 2-carboxifenil, 2-tetrazolilfenil, 2-(propilu-
reidosulfonil)fenil o 2-(fenilcarboxamidosulfonil)fenil.
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. Uso según cualquiera de las reivindicaciones 1 a 5, caracterizado porque R3 es un átomo de hidrógeno o de halógeno; alquilo(C1-C4); cicloalquilo(C3-C6); 1-hidroxialquilo(C1-C6); alquiltio(C1-C4); carboxi; o alcoxicarbonil (C1-C6).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. Uso según la reivindicación 6, caracterizado porque R3 es hidrógeno, cloro, 1-hidroxi-1-metiletil o metiltio.7. Use according to claim 6, characterized in that R3 is hydrogen, chlorine, 1-hydroxy-1-methylethyl or methylthio. 8. Uso según cualquiera de las reivindicaciones 1 a 7, caracterizado porque R4 es un radical hidroxialquil (C1-C6); carboxi, donde dicho carboxi puede estar opcionalmente sustituido por 1-(etoxicarboniloxi)etil, 5-metil-2-oxo-1,3-dioxol-4-ilmetil o alquilo (C1-C4); carboxialquenil, donde dicho carboxialquenil puede estar opcionalmente sustituido por aril, arilalquil, o heteroaril; o ariltioalquil, donde dicho ariltioalquil puede estar opcionalmente sustituido por alquilo (C1-C4), carboxi o alcoxi (C1-C4).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. Uso según la reivindicación 8, caracterizado porque R4 es hidroximetil, carboxi, 1-(etoxicarboniloxi)etoxicarbonil, 5-metil-2-oxo-1,3-dioxol-4-ilmetiloxicarbonil, 2-carboxi-3-(2-tienil)-1-propenil, 2-carboxi-3-fenil-1-propenil o 2-carboxifeniltiometil.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. 10. Uso según cualquiera de las reivindicaciones 1 a 5, caracterizado porque dicho sistema bicíclico es 6-(hidroximetil)bencimidazol, 7-carboxibencimidazol,7-[1-(ciclohexiloxicarboniloxi) etoxicarbonil] bencimidazol, 4-metil-6-(1-metil-1H-bencimidazol-2-il)bencimidazol, 4-metil-6-(5,6,7,8-tetrahidroimidazo[1,2-a]piridin-2-il)bencimidazol, 3H-imidazo[4,5-b]piridina, 5-carboxi-7-metil-3H-imidazo[4,5-b]piridina, 7-metil-3H-imidazo[4,5-b]piridina, 5,7-dimetil-3H-imidazo[4,5-b]piridina, 7-(hidroximetil)-3H-imidazo[4,5-b]piridina, 5-(2-tienilmetil)-4,5-dihidro-3H-imidazo[4,5-c]piridin-4-ona o 5-(2-metoxicarbonil)bencil-4,5-dihidro-3H-imidazo[4,5-c]piridin-4-ona.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. Uso según la reivindicación 1, caracterizado porque dicho derivado de imidazol es 2-Butil-4-cloro-5-(hidroxi-
metil)-1-[2'-(1H-tetrazol-5-il)bifenil-4-ilmetil]imidazol.
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.
12. Uso según la reivindicación 1, caracterizado porque dicho derivado de imidazol es ácido 3-[2-butil-1-(4-carboxibencil)-1H-imidazol-5-il]-2-(2- tienilmetil)-2(E)-propenoico.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. Uso según la reivindicación 1, caracterizado porque dicho derivado de imidazol es ácido (\pm)-2-etoxi-1-[2'-(1H-tetrazol-5-il)bifenil-4-ilmetil]-1H- benzimidazol-7-carboxílico 1-(ciclohexiloxicarboniloxi)etil éster.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. Uso según la reivindicación 1, caracterizado porque dicho derivado de imidazol es ácido 4'-[4-Metil-6-(1-metil-1H-bencimidazol-2-il)-2-propil-1H- bencimidazol-1-ilmetil]bifenil-2-carboxílico.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. 15. Uso según cualquiera de las reivindicaciones 1 a 14, caracterizado porque es para la fabricación de un medicamento para el tratamiento de un trastorno que viene mediado por el péptidoleucotrieno LTD_{4}.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. 16. Uso según cualquiera de las reivindicaciones 1 a 15, caracterizado porque es para la fabricación de un medicamento para el tratamiento de un trastorno que viene mediado por el péptidoleucotrieno LTC_{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. Uso según cualquiera de las reivindicaciones 1 a 16, caracterizado porque es para la fabricación de un medicamento para el tratamiento de asma bronquial.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. Uso según cualquiera de las reivindicaciones 1 a 16, caracterizado porque es para la fabricación de un medicamento para el tratamiento de bronquitis crónica.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. Uso según cualquiera de las reivindicaciones 1 a 16, caracterizado porque es para la fabricación de un medicamento para el tratamiento de sinusitis eosinofílica.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. Uso según cualquiera de las reivindicaciones 1 a 16, caracterizado porque es para la fabricación de un medicamento para el tratamiento de otitis media.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. Uso según cualquiera de las reivindicaciones 1 a 16, caracterizado porque es para la fabricación de un medicamento para el tratamiento de urticaria crónica.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. Uso según cualquiera de las reivindicaciones 1 a 16, caracterizado porque es para la fabricación de un medicamento para el tratamiento de poliposis nasal.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. Uso según cualquiera de las reivindicaciones 1 a 16, caracterizado porque es para la fabricación de un medicamento para el tratamiento de gastroenteritis eosinofílica.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. Uso según cualquiera de las reivindicaciones 1 a 16, caracterizado porque es para la fabricación de un medicamento para el tratamiento de mastocitosis.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. Uso según cualquiera de las reivindicaciones 1 a 16, caracterizado porque es para la fabricación de un medicamento para el tratamiento de fibrosis pulmonar idiopática.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. Uso según cualquiera de las reivindicaciones 1 a 16, caracterizado porque es para la fabricación de un medicamento para el tratamiento de anafilaxis cardíaca.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.
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