WO2007028524A2 - Utilisation d'un derive d'imidazole - Google Patents

Utilisation d'un derive d'imidazole Download PDF

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Publication number
WO2007028524A2
WO2007028524A2 PCT/EP2006/008427 EP2006008427W WO2007028524A2 WO 2007028524 A2 WO2007028524 A2 WO 2007028524A2 EP 2006008427 W EP2006008427 W EP 2006008427W WO 2007028524 A2 WO2007028524 A2 WO 2007028524A2
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WO
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Prior art keywords
carboxy
use according
alkyl
replaced
optionally
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PCT/EP2006/008427
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English (en)
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WO2007028524A3 (fr
Inventor
Josep Prous Blancafort
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Prous Institute For Biomedical Research S.A.
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Publication of WO2007028524A2 publication Critical patent/WO2007028524A2/fr
Publication of WO2007028524A3 publication Critical patent/WO2007028524A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic 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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic 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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic 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
    • A61K31/4353—Heterocyclic 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
    • A61K31/437—Heterocyclic 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders

Definitions

  • the present invention relates to the use of derivatives of imidazole having the general formula (I),
  • inhaled corticosteroids in the treatment of asthmatic processes, apart from its efficiency, has some undesired effects as well as its toxicity, particularly in children. Moreover, in a considerable number of patients, it does not achieve the desired necessary therapeutic control, and therefore it is important to find new anti-asthmatic agents that have fewer side effects.
  • One of the new therapeutic approaches is the use of peptidoleukotriene antagonists, which in addition to their bronchodilator potential, also show anti- inflammatory activity.
  • leukotrienes are derived from arachidonic acid, a fatty acid that is released from the phospholypid containing it due to the action of phospholipase A 2 .
  • Arachidonic acid is metabolised in turn mainly by two different enzymatic systems. One, through cyclooxygenase, produces tromboxane and prostaglandins, involved in inflammatory conditions, but which also play a part in functions such as muscular contraction, calcium transportation, hormone regulation and cell growth control.
  • LTD 4 is a powerful bronchoconstrictor, while also inducing smooth muscle contraction, myocardial depression, an increase in vascular permeability and the production of mucous (Marom et al . , Am. Rev. Resp. Dis., 126, 449 (1982)), whereby it is directly involved in the following pathologies:
  • both LTC 4 and LTD 4 cause an exaggerated contraction of the cardiac fabric and therefore it has been suggested to use them 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)).
  • the present invention describes a series of derivatives of imidazole (currently used as antihypertensive agents) that are leukotriene and/or peptidoleukotriene antagonists, particularly vis-a-vis the peptidoleukotriene LTD 4 and/or the peptidoleukotriene LTC 4 .
  • These derivatives of imidazole having the general formula I, where Rl, R2, R3 and R4 have the meaning indicated below, are useful in the treatment of several diseases and condition changes that are likely to show improvement through the antagonism of leukotrienes and peptidoleukotrienes, which was unknown until now, such as for example, those indicated above, and, therefore, they are useful for producing medicines for the treatment thereof.
  • bronchial asthma chronic bronchitis, eosinophilic sinusitis, otitis media, chronic urticaria, nasal polyposis, eosinophilic gastroenteritis, mastocytosis, idiopathic pulmonary fibrosis and/or cardiac anaphylaxis .
  • the present invention relates to the use of derivates of imidazole having the general formula (I)
  • 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-
  • R4 is a radical hydroxy,- hydroxyalkyl (Cl -C6) ; alkoxy (C1-C6) ; cycloalkyl (C3-C8); cycloalkoxy (C3-C8); amino; alkylamino (C1-C6) ; carboxy, where said carboxy can be optionally replaced leading to a physiologically acceptable ester; alkyl (C1-C6) ; alkenyl (C2-C6) , where said alkyl (Cl- C6) or alkenyl (C2-C6) can be optionally 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 (Cl- C4) ; aryl; heteroaryl; aryloxy;
  • 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,-
  • Rl is a radical alkyl (C1-C4) ; cycloalkyl (C3-C6) or alkoxy (C1-C4) ; more preferably Rl is a radical ethyl, propyl, cyclopropyl, butyl or ethoxy,-
  • R2 is a carboxy group,- alcoxycarbonyl (C1-C6) ,- or a phenyl group, where said phenyl is replaced in the ortho position of the ring by an acid group selected from the group made up of carboxy, tetrazole, alkylureidosulphonyl and arylcarboxamidosulphonyl; more preferably R2 is carboxy, 2- carboxyphenyl , 2-tetrazolylphenyl, 2- (propylureidosulphonyl) phenyl or 2-
  • R3 is a hydrogen or halogen atom; alkyl (Cl -C4) ; cycloalkyl (C3-C6); 1-hydroxyalkyl (C1-C6) ; alkylthio (Cl- C4) ; carboxy; or alkoxycarbonyl (C1-C6) ; more preferably R3 is hydrogen, chlorine, 1 -hydroxy-1-methylethyl or methylthio,-
  • R4 is a radical hydroxyalkyl (C1-C6) ; carboxy, where optionally said carboxy can be replaced by 1- (ethoxycarbonyloxy) ethyl, 5-methyl-2-oxo-l, 3-dioxol-4-ylmethyl or alkyl (C1-C4) ; carboxyalkenyl, where optionally said carboxyalkenyl can be replaced by aryl, arylalkyl, or heteroaryl; or arylthioalkyl, where optionally said arylthioalkyl can be replaced by alkyl (C1-C4) , carboxy or alkoxy (C1-C4) ; more preferably R4 is hydroxymethyl , carboxy, 1- (ethoxycarbonyloxy) ethoxycarbonyl , 5-methyl-2-oxo-l , 3- dioxol-4-ylmethyloxycarbonyl , 2-carboxy-3- (2-tienyl) -1- propenyl, 2
  • R3 and R4 can make up, together with the imidazole ring to which they are attached, a bicyclical system.
  • Preferred bicyclical systems are benzimidazole, imidazopyridine, imidazopyrimidine, thienoimidazole, imidazopyrazole, imidazopyridone or imidazopyridazinone.
  • the bicyclical systems are 6- (hydroxymethyl) benzimidazole, 7-carboxybenzimidazol, 7- [1- (cyclohexyloxycarbonyloxy) ethoxycarbonyl] benzimidazole, 4- methyl-6- (l-methyl-lH-benzimidazole-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 ,
  • the compounds of this invention are leukotriene and peptidoleukotriene antagonists and show marked selectivity for LTD4, which makes them particularly useful as therapeutic agents in pathologies where a marked LTD4 effect is observed, such as for example asthma, allergic rhinitis, chronic obstructive pulmonary disease, etc.
  • the object of the invention is also the use of derivates of imidazole having formula (I) for manufacturing medicines intended for treating pathologies where a marked effect of LTD4 is observed, particularly for manufacturing a medicine for treating respiratory diseases and for those where a predominant role of the inflammatory processes has been described such as allergies, autoimmune diseases, cardiovascular and cerebrovascular diseases, and cancer.
  • the compounds having general formula (I) can be synthesised according to the procedures described in various patent applications, 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 pic) .
  • EP 0546358 Takeda Pharm. Co., Ltd.
  • WO 2001001987 (AstraZeneca pic)
  • WO 2005020971 (AstraZeneca pic )
  • Illustrative examples of compounds comprised in this invention include the compounds that are characterised with the data indicated in Tables 1 to 4.
  • the method's principle consists in evaluating the inhibition of the link of the receptor's specific ligand (radioactively marked) vis-a-vis a determined concentration of the described compounds.
  • CHO-Kl cells were used, which express the recombinant human receptor.
  • specific ligand [3H] peptidoleukotriene D 4 (0.3 nM) was used, and a concentration of 300 nM of the peptidoleukotriene D 4 was used as the control for the non-specific link.
  • different concentrations (1-10 ⁇ M) were used, and in the case of examples 1,2 and 12, a concentration of 10 ⁇ M was used.
  • the studies were carried out in duplicate.
  • Table 5 shows the results obtained in examples 1, 2, 11 and 12.
  • This invention relates, also, to pharmaceutical compositions comprising, as the active ingredient, at least one derivate having the formula (I) or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient or diluent.
  • compositions are in an appropriate form for oral, topical, inhaled, rectal, transdermal, nasal or parenteral administration.
  • pharmaceutically acceptable excipients or diluents which are mixed with the active compound or compounds to form the compositions in this invention, are well known per se and the real excipients used depend on the method used for administering the compositions.
  • compositions for oral administration can adopt the form of tablets, capsules, pills, or effervescent granules or liquid preparations such as elixirs, syrups or suspensions, all of which contain one or more invention compounds.
  • Such preparations can be carried out using well known methods, for example by mixing the formula derivatives with the pharmaceutically acceptable excipients and diluents.
  • the diluents that can be used to prepare the compositions include liquid and solid diluents, which are compatible with the active ingredients, together with colouring or sweetening agents, if desired.
  • the tablets or capsules can contain between 0.1 and 100 mg of the active ingredient.
  • the compounds can also be incorporated into pellets coated with natural or synthetic polymers known in the art for producing controlled release characteristics, or polymers can be included in the tablets to produce the same characteristics.
  • the liquid compositions suitable for oral use can adopt the form of solutions, suspensions or aerosols.
  • the suspensions can include an insoluble or microencapsulated form of the invention's active compound together with water and other acceptable solvents, and a thickening or sweetening agent.
  • compositions for inhaled administration can adopt 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.

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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)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pulmonology (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne l'utilisation d'un dérivé d'imidazole et en particulier l'utilisation d'un dérivé d'imidazole représenté par la formule (I) dans laquelle: R1 désigne un radical hydroxy; alkyle (C1-C6) linéaire ou ramifié; alcoxy (C1-C6); cycloalkyle (C3-C8); cycloalcoxy (C3-C8); ou carboxy, carboxy pouvant éventuellement être remplacé par un groupe alkyle (C1-C6) linéaire ou ramifié; R2 désigne un groupe carboxy; alcoxycarbonyle (C1-C10); ou un groupe phényle, ledit groupe phényle pouvant éventuellement être remplacé en position ortho par un groupe acide; R3 désigne un atome d'hydrogène ou un atome d'halogène; un radical hydroxy; carboxy, alkyle (C1-C6); hydroxyalkyle (C1-C6); alcoxy (C1-C6); cycloalkyle (C3-C8); cycloalcoxy (C3-C8); amino; alkylthio (C1-C6); cycloalkylthio (C3-C8); aryle; hétéroaryle; aryloxy; hétéroaryloxy; arylthio; ou hétéroarylthio, aryle, hétéroaryle, aryloxy, hétéroaryloxy, arylthio ou hétéroarylthio pouvant être remplacé par alkyle (C1-C4), halogène, alcoxy (C1-C4), amino, alkylamino (C1-C4), carboxy ou alcoxycarbonyle (C1-C6); R4 désigne un radical hydroxy; hydroxyalkyle (C1-C6); alcoxy (C1-C6); cycloalkyle (C3-C8); cycloalcoxy (C3-C8); amino; alkylamino (C1-C6); carboxy, carboxy pouvant éventuellement être remplacés, produisant un ester physiologiquement acceptable; alkyle (C1-C6); alcényle (C2-C6), alkyle (C1-C6) et alcényle (C2-C6) pouvant éventuellement être remplacés par carboxy, aryle, arylalkyle, hétéroaryle ou arylthio, carboxy, aryle, arylalkyle, hétéroaryle et arylthio pouvant à leur tour être éventuellement remplacés par alkyle (C1-C4), carboxy ou alcoxy (C1-C4); aryle; hétéroaryle; aryloxy; ou hétéroaryloxy, aryle, hétéroaryle, aryloxy ou hétéroaryloxy pouvant éventuellement être remplacés par alkyle (C1-C4), halogène, alcoxy (C1-C4), amino, alkylamino (C1-C4), carboxy ou alcoxycarbonyle (C1-C6); ou R3 et R4 peuvent former, avec les atomes du noyau imidazole auquel il sont fixés, un système bicyclique, ledit système bicyclique étant benzimidazole, imidazopyridine, imidazopyrimidine, thienoimidazole, imidazopyrazole, imidazopyridone ou imidazopyridazinone; ou d'un des sels ou solvates physiologiquement acceptables de celui-ci, pour produire un médicament servant au traitement d'un trouble impliquant un leucotriène ou un peptidoleucotriène.
PCT/EP2006/008427 2005-09-06 2006-08-29 Utilisation d'un derive d'imidazole WO2007028524A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ES200502163A ES2246742B1 (es) 2005-09-06 2005-09-06 Uso de un derivado de imidazol.
ES200502163 2005-09-06

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WO2007028524A2 true WO2007028524A2 (fr) 2007-03-15
WO2007028524A3 WO2007028524A3 (fr) 2007-05-31

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Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2246742B1 (es) * 2005-09-06 2007-02-01 Prous Institute For Biomedical Research S.A. Uso de un derivado de imidazol.

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0502314A1 (fr) * 1991-02-06 1992-09-09 Dr. Karl Thomae GmbH Benzimidazoles, médicaments les contenant et procédé pour leur préparation
US5391758A (en) * 1985-04-17 1995-02-21 Zeneca, Inc. Heterocyclic amide derivatives
EP0882718A1 (fr) * 1995-12-28 1998-12-09 Fujisawa Pharmaceutical Co., Ltd. Derives du benzimidazole
WO2000038676A1 (fr) * 1998-12-23 2000-07-06 Novartis Ag Utilisation d'un antagoniste du recepteur d'at-1 ou d'un modulateur du recepteur d'at-2 pour traiter des affections associees a une augmentation des recepteurs d'at-1 ou d'at-2
WO2005020971A1 (fr) * 2003-08-29 2005-03-10 Astrazeneca Ab Utilisation d'un antagoniste de l'angiotensine ii pour la prevention de l'infarctus du myocarde
ES2246742A1 (es) * 2005-09-06 2006-02-16 Prous Science, S.A. Uso de un derivado de imidazol.

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU658729B2 (en) * 1992-03-27 1995-04-27 Kyoto Pharmaceutical Industries, Ltd. 3-(1H-imidazol-1-ylmethyl)-1H-indole derivatives

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5391758A (en) * 1985-04-17 1995-02-21 Zeneca, Inc. Heterocyclic amide derivatives
EP0502314A1 (fr) * 1991-02-06 1992-09-09 Dr. Karl Thomae GmbH Benzimidazoles, médicaments les contenant et procédé pour leur préparation
EP0882718A1 (fr) * 1995-12-28 1998-12-09 Fujisawa Pharmaceutical Co., Ltd. Derives du benzimidazole
WO2000038676A1 (fr) * 1998-12-23 2000-07-06 Novartis Ag Utilisation d'un antagoniste du recepteur d'at-1 ou d'un modulateur du recepteur d'at-2 pour traiter des affections associees a une augmentation des recepteurs d'at-1 ou d'at-2
WO2005020971A1 (fr) * 2003-08-29 2005-03-10 Astrazeneca Ab Utilisation d'un antagoniste de l'angiotensine ii pour la prevention de l'infarctus du myocarde
ES2246742A1 (es) * 2005-09-06 2006-02-16 Prous Science, S.A. Uso de un derivado de imidazol.

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ES2246742A1 (es) 2006-02-16
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