WO1996019991A1 - Benzimidazoles utilises comme inhibiteurs du metabolisme du calcitriol - Google Patents

Benzimidazoles utilises comme inhibiteurs du metabolisme du calcitriol Download PDF

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WO1996019991A1
WO1996019991A1 PCT/EP1995/005172 EP9505172W WO9619991A1 WO 1996019991 A1 WO1996019991 A1 WO 1996019991A1 EP 9505172 W EP9505172 W EP 9505172W WO 9619991 A1 WO9619991 A1 WO 9619991A1
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Prior art keywords
substituted
alkyl
phenyl
calcitriol
cycloalkyl
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PCT/EP1995/005172
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English (en)
Inventor
Hugo Florent Adolf Vanden Bossche
Gustaaf Henri Maria Willemsens
Roland De Coster
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Janssen Pharmaceutica N.V.
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Priority to EP95943236A priority Critical patent/EP0800391A1/fr
Priority to JP8520221A priority patent/JPH10511653A/ja
Priority to AU44361/96A priority patent/AU4436196A/en
Publication of WO1996019991A1 publication Critical patent/WO1996019991A1/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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention is concerned with the use of (1H-imidazol-1-yl)methyl-1H-benzimidazoles for the manufacture of a medicament for treating a pathological condition which is beneficially influenced by inhibiting the metabolic degradation of calcitriol.
  • Calcitriol (generic to l ⁇ ,25-dihydroxy-vitamin D 3 ) is endogenously formed from vitamin D 3 by metabolic reactions and appears to carry out all the functions attributed to the vitamin D hormone system.
  • Vitamin D compounds are involved in the regulation of calcium and phosphate homeostasis and bone mineralisation.
  • the daily requirements of vitamin D are met by exposure to sunlight and/or obtained from the diet. In case of inadequate exposure to sunlight and/or a lack of the vitamin in the diet, problems of vitamin D deficiency may arise. These problems are further aggravated by the rapid metabolism of calcitriol to inactive compounds.
  • calcitriol has been described to show antiinflammatory and immunomodularing activity. It has also been shown that calcitriol stimulates the differentiation of cells and has inhibitory activity on cell proliferation. Moreover, the compound has potential use in the treatment of hypertension and diabetes mellitus. The therapeutic potential of exogenously administered calcitriol, however, is limited by its rapid metabolic degradation. Furthermore, excessive intake of the compound leads to the development of adverse effects. (1H-imidazol-1-yl)methyl-1H-benzimidazoles have been described in EP-0,260,744 having inhibitory activity on androgen formation and are useful in preventing or therapeutically treating androgenic hormone dependent disorders. EP-0,371,559 discloses the use of these compounds to suppress the metabolism of retinoids.
  • Said property can be used to control the rate of growth and differentiation of normal, preneoplastic and neoplastic epithelial cells, thus making these compounds useful in the treatment of carcinoma and keratinization disorders.
  • the (+) isomer of 5-[3-chlorophenyl]-1H-imidazol-1-ylmethyl]-1H-benzimidazole has been described in WO 95/22540, published on August 24, 1995, as being particularly useful in the field of dermatology.
  • the (-) isomer of 5-[3-chlorophenyl]-1H-imidazol-1-ylmethyl]-1H-benzimidazole has been described in WO 95/22541, published on August 24, 1995, as being particularly useful in the field of oncology.
  • the (1H-imidazol-1-yl)methyl-1H-benzimidazoles described in the present invention inhibit the metabolic degradation of calcitriol and overcome certain problems associated with art known vitamin D therapy.
  • the present invention relates to the use of (1H-imidazol-1-yl)methyl-1H-benzimidazoles, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, for the manufacture of a medicament for treating a pathological condition which is beneficially influenced by inhibiting the metabolic degradation of calcitriol, said benzimidazoles having the formula
  • R is hydrogen; C 1- 10 alkyl; C 3-7 cycloalkyl; Ar 1 or Ar 1 -C 1-6 alkyl;
  • R 1 is hydrogen; C 3-7 cycloalkyl; Ar 1 ; C 1-10 alkyl; C 1 -6 alkyl substituted with Ar 1 or C 3-7 cycloalkyl; hydroxy; C 1- 10 alkyloxy; C 1-6 alkyloxy substituted with Ar 1 or
  • R 2 is hydrogen; halo; C 1- 10 alkyl; C 1-4 alkyl substituted with up to 4 halo atoms;
  • each Ar 1 independently is phenyl, substituted phenyl, pyridinyl, aminopyridinyl, imidazolyl, thienyl, halothienyl, furanyl, halofuranyl or thiazolyl;
  • each Ar 2 independently is phenyl or substituted phenyl
  • said substituted phenyl represents phenyl substituted with 1, 2 or 3 substituents each independently selected from halo, hydroxy, trifluoromethyl,
  • halo is generic to fluoro, chloro, bromo and iodo;
  • C 1 -4 alkyl is meant to include straight and branch chained saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl.
  • C 1-6 alkyl includes C 1-4 alkyl radicals and the higher homologs thereof having 5 or 6 carbon atoms
  • C 1-10 alkyl is meant to include C 1-6 alkyl radicals, as defined hereinabove, and the higher homologs thereof having from 7 to 10 carbon atoms
  • C 3-7 cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl
  • C 3-6 alkenyl defines straight chained and branched hydrocarbon radicals containing one double bond having from 3 to 6 carbon atoms such as, for example, 3-propenyl, 2-butenyl and the like
  • C 3-6 alkynyl defines straight chained and branched hydrocarbon radicals containing one triple bond and having from 3
  • addition salts as mentioned herein are meant to comprise the therapeutically active addition salt forms which the compounds of formula (I) are able to form with appropriate acids, such as, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.
  • inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid
  • sulfuric nitric; phosphoric and the like acids
  • the pharmaceutically acceptable addition salts as mentioned hereinabove are also meant to comprise the therapeutically active non-toxic base, in particular, a metal or amine addition salt forms which the compounds of formula (I) are able to form.
  • Said salts can conveniently be obtained by treating the compounds of formula (I) containing acidic hydrogen atoms with appropriate organic and inorganic bases such as, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
  • organic bases e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like
  • salt forms can be converted by treatment with an appropriate base or acid into the free acid or base form.
  • addition salt as used hereinabove also comprises the solvates which the compounds of formula (I) are able to form and said solvates are meant to be included within the scope of the present invention. Examples of such solvates are, e.g. the hydrates, alcoholates and the like.
  • the compounds of formula (I) wherein R is other than hydrogen have an asymmetric carbon atom in their structure, the absolute configuration of which may be represented by the descriptors R and S.
  • Formula (I) is intended to encompass all enantiomers and diastereoisomers of the compounds of the invention as well as the mixtures thereof, in particular the racemates and the enantiomerically pure forms (i.e. the enantiomeric excess is equal to or higher than 95%).
  • the compounds of formula (I) may contain in their structure a tautomeric system and, consequently, these compounds can be represented by each of their tautomeric forms. All tautomeric forms are meant to be embraced by the definition of the compounds of formula (I).
  • the present invention is concerned with the use of a compound of formula (I) wherein R is phenyl or substituted phenyl; R 1 is hydrogen or C 1-6 alkyl; R 2 is hydrogen; halo; C 1-6 alkyl; C 1-4 alkyl substituted with up to 4 halo atoms;
  • More interesting compounds are the compounds of formula (I) wherein the 1H-imidazol-1-ylmethyl moiety is substituted on either the 5 or 6 position of the benzimidazole ring.
  • R 1 is hydrogen
  • R 2 is hydrogen, C 1-6 alkyl or phenyl
  • the preferred compounds within the invention are ( ⁇ )-5-[(3-chlorophenyl)(1H-imidazol-1-yl)methyl]-1H-benzimidazole (generically known as liarozole), (+)-liarozole, (-) liarozole and the pharmaceutically acceptable addition salts thereof, in particular, the hydrochloride and the fumarate salts such as, for example, liarozole hydrochloride, liarozole fumarate, (+)-liarozole hydrochloride and (-)-liarozole hydrochloride.
  • Vitamin D 3 is sequentially metabolized by enzymes, first to 25-hydroxy-vitamin D 3 in the liver and then to either 24,25-dihydroxy-vitamin D 3 or the active hormonal form 1 ⁇ ,25-dihydroxy-vitamin D 3 in the kidney.
  • Vitamin D 3 (generically known as cholecalciferol) and 25-hydroxy-vitamin D 3 (generically known as calcifediol), therefore, are prodrugs of the subject active compound calcitriol.
  • Another prodrug of calcitriol is 1 ⁇ -hydroxy-vitamin D 3 (generically known as alfacalcidol), which is hydroxylated at the 25 position in the liver to give calcitriol.
  • Calcitriol is further metabolized to inactive degradation products, e.g. in the kidney and the skin.
  • the compounds of formula (I) are useful in inhibiting the metabolic degradation of endogenously formed and exogenously administered calcitriol.
  • the inhibitory activity of the compounds of formula (I) on the metabolic degradation of calcitriol is evidenced by measuring the impact of said compounds on the calcitriol degradation in human foreskin keratinocytes, pig kidney cells and human hepatoma cells, as described hereinafter.
  • the therapeutic potential of the compounds of formula (I), optionally in combination with calcitriol or a prodrug thereof, preferably, cholecalciferol, calcifediol or alfacalcidol extends to all pathological conditions which are beneficially influenced by inhibiting the metabolic degradation of calcitriol.
  • the compounds of formula (I) optionally in combination with calcitriol or a prodrug thereof, preferably, cholecalciferol, calcifediol or alfacalcidol can be useful in the treatment of vitamin D deficiency states.
  • Vitamin D deficiency may arise from inadequate exposure to sunlight and/or from a lack of the vitamin in the diet and is further aggravated by the rapid metabolic degradation of calcitriol, and leads to a syndrome characterized by hypocalcaemia, hypophosphataemia, bone softening and bone pain.
  • Other clinical applications of the compounds of formula (I) optionally in combination with calcitriol or a prodrug thereof, preferably, cholecalciferol, calcifediol or alfacalcidol, are reviewed by Bouillon et al., Endocrine Reviews (1995) 16(2), 200-257 and include metabolic bone disorders, e.g.
  • osteoporosis osteopetrosis and the like; primary and depoty hyperparathyroidism; renal osteodystrophy; diseases of the immune system or other conditions characterized by an abnormal interleukin production, e.g. inflammatory diseases such as rheumatoid arthritis and asthma; hypertension; diabetes mellitus;
  • cancer e.g. leukemia, carcinoma, sarcoma, lymphoma and the like
  • keratinization disorders e.g. acne, psoriasis, lamellar ichthyosis, plantar warts, callosities, acanthosis nigricans, lichen planus, molluscum, melasma, corneal epithelial abrasion, geographic tongue, Fox-Fordyce disease, cutaneous metastatic melanoma and keloids, epidermolytic hyperkeratosis, Darier's disease, pityriasis rubra pilaris, congenital ichthyosiform erythroderma, hyperkeratosis palmaris et plantaris, and similar disorders.
  • cancer e.g. leukemia, carcinoma, sarcoma, lymphoma and the like
  • keratinization disorders e.g. acne, psoriasis
  • the present invention concerns the use of (1H-imidazol-1-yl)methyl-1H-benzimidazoles of formula (I) for the manufacture of a medicament for treating a pathological condition which is beneficially influenced by inhibiting the metabolic degradation of calcitriol. Also, the present invention concerns a method of treating patients suffering from a pathological condition which is beneficially influenced by inhibiting the metabolic degradation of calcitriol, said method consisting of administering to a patient an effective amount of a compound of formula (I), an addition salt or a stereochemically isomeric form thereof.
  • Another aspect of the incvention concerns the use of (1H-imidazol-1-yl)methyl-1H-benzimidazoles of formula (I) in combination with calcitriol or a prodrug thereof for the manufacture of a medicament for treating a pathological condition which is beneficially influenced by inhibiting the metabolic degradation of calcitriol.
  • this aspect of the invention concerns a method of treating patients suffering from a pathological condition which is beneficially influenced by inhibiting the metabolic degradation of calcitriol, in particular keratinization disorders such as psoriasis, said method consisting of administering to a patient (a) an effective amount of calcitriol or a prodrug thereof and (b) an effective amount of a compound of formula (I), an addition salt or a stereochemically isomeric form thereof.
  • the invention relates to a single drug therapy involving a compound of formula (I), as well as a combination therapy including a compound of formula (I) and calcitriol or a prodrug thereof.
  • the active ingredients each independently may be administered orally, rectally, percutaneously, topically or by parenteral injection, depending on the affliction to be treated and the evaluation of the physician prescribing the treatment with the subject drugs.
  • the drugs each independently are administered orally or topically.
  • the compounds of formula (I) and calcitriol or a prodrug thereof may be administered separately (i.e. simultaneously, concurrently or consecutively) or the different drugs may be combined in one dosage form.
  • a particular embodiment of the invention relates to a product containing (a) a
  • the product contains (a) a pharmaceutical composition containing an effective amount of calcitriol or a prodrug thereof and (b) a pharmaceutical composition containing an effective amount of ( ⁇ )-5-[(3-chlorophenyl)(1H-imidazol-1-yl)methyl]-1H-benzimidazole (generically known as liarozole), (+)-liarozole, (-) liarozole or a pharmaceutically acceptable addition salt thereof, in particular, liarozole hydrochloride, liarozole fumarate, (-f-)-liarozole hydrochloride and (-)-liarozole hydrochloride.
  • Such products may comprise, for example, a kit comprising a container with a suitable composition containing calcitriol or a prodrug thereof and another container comprising a compound of formula (I), an addition salt or a stereochemically isomeric form thereof.
  • Such a product may have the advantage that a physician can select on the basis of the diagnosis the appropriate amounts of each component and the sequence and timing of the administration thereof.
  • the drugs are preferably formulated in specific compositions thereof.
  • compositions there may be cited all compositions usually employed for systemically or topically administering drugs.
  • compositions of this invention an effective amount of the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • a pharmaceutically acceptable carrier which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral hquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules, and tablets.
  • tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed.
  • the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included.
  • injectable solutions for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution.
  • injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin.
  • a penetration enhancing agent and/or a suitable wetting agent optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin.
  • suitable additives e.g. creams, gels, dressings, shampoos, tinctures, pastes, ointments, salves, powders and the like.
  • compositions may be by aerosol, e.g. with a propellent such as nitrogen carbon dioxide, a freon, or without a propellent such as a pump spray, drops, lotions, or a semisolid such as a thickened composition which can be applied by a swab.
  • a propellent such as nitrogen carbon dioxide, a freon
  • a propellent such as a pump spray
  • drops lotions
  • a semisolid such as a thickened composition which can be applied by a swab.
  • ⁇ -, ⁇ - or ⁇ -cyclodextrins or their derivatives in particular hydroxyalkyl substituted cyclodextrins, e.g.
  • Dosage unit form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets
  • compositions are preparations of the cosmetic type, such as toilet waters, lotions, skin milks or milky lotions.
  • Said preparations contain, besides the active ingredients, components usually employed in such preparations.
  • components usually employed in such preparations.
  • examples of such components are oils, fats, waxes, surfactants, humectants, thickening agents, antioxidants, viscosity stabilizers, chelating agents, buffers, preservatives, perfumes, dvestuffs, lower alkanols, and the like.
  • covers may be used, e.g. plasters, bandages, dressings, gauze pads and the like, containing an appropriate amount of a composition as referred hereinabove.
  • covers may be applied which have been impregnated or sprinkled with a liquid formulation containing the active agents, or strewn with a powdery solid composition, or smeared, covered or coated with a semiliquid composition.
  • compositions are those adapted for topical administration.
  • the latter compositions comprise a skin-acceptable carrier, an effective amount of a compound of formula (I), an addition salt or a stereochemically isomeric form thereof, and an effective amount of calcitriol or a prodrug thereof.
  • an effective daily dose of a compound of formula (I), an addition salt or a stereochemically isomeric form thereof would be from 0.001 mg/kg to 20 mg/kg body weight and more preferably from 0.01 mg/kg to 10 mg/kg body weight.
  • the effective daily dose of calcitriol or a prodrug thereof ranges from about 0.1 ⁇ g to about 10 mg, in particular from about 0.5 ⁇ g to about 1 mg and preferably from about 1 ⁇ g to about 0.1 mg. It may be appropriate to administer the required dose as several sub-doses at appropriate intervals throughout the day.
  • (+)-liarozole hydrochloride, (-)-liarozole hydrochloride or ( ⁇ )-liarozole hydrochloride is suitably administered b.i.d..
  • compositions for topical application comprise from 0.005 to 0.5% w/w (particularly from 0.01 to 0.1%) calcitriol and/or from 0.05 to 5% of (+)-liarozole hydrochloride, (-)-liarozole hydrochloride or ( ⁇ )-liarozole hydrochloride, in a semi-solid or liquid diluent or carrier.
  • the topical compositions are applied to the area to be treated or protected at regular intervals as needed, generally about 7 to about 21 times per week. The duration of the treatment will depend upon the nature and severity of the condition to be treated as well as the frequency of application of the composition.
  • Active ingredient 1 (A.I. 1) as used throughout these examples relates to a compound of formula (I), a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof.
  • Active ingredient 2 (A.I. 2) relates to calcitriol or a prodrug thereof. Formulations containing a single active ingredient as well as those comprising both active ingredients are exemplified.
  • 75 mg stearyl alcohol, 2 mg cetyl alcohol, 20 mg sorbitan monostearate and 10 mg isopropyl myristate are introduced into a doublewall jacketed vessel and heated until the mixture has completely molten.
  • This mixture is added to a separately prepared mixture of purified water, 200 mg propylene glycol and 15 mg polysorbate 60 having a temperature of 70 to 75°C while using a homogenizer for liquids.
  • the resulting emulsion is allowed to cool to below 25°C while continuously mixing.
  • a mixture of 2 g A.I. 1 and/or 0.02 g A.I. 2 microfine, 20 g phosphatidyl choline, 5 g cholesterol and 10 g ethyl alcohol is stirred and heated at 55-60°C until complete dissolution and is added to a solution of 0.2 g methyl paraben, 0.02 g propyl paraben,
  • a mixture of 10 g phosphatidyl choline and 1 g cholesterol in 7.5 g ethyl alcohol is stirred and heated at 40°C until complete dissolution.
  • 2 g A.I. 1 and/or 0.02 g A.I. 2 microfine is dissolved in purified water by mixing while heating at 40°C.
  • the alcoholic solution is added slowly to the aqueous solution while homogenizing during 10 minutes.
  • Example 10 Metabolism of calcitriol by human foreskin keratinocytes, pig kidney cells and human hepatoma cells
  • the dermal and epidermal tissues of human foreskin was cut in 0.5 cm ⁇ pieces and incubated overnight at 4°C in 10 ml phosphate buffer (PBS) without calcium and magnesium, containing 2 ml Dispase II (a protease supplied by Boehringer Mannheim at an activity of 24U/ml). After incubation, the tissue was placed in 15 ml trypsin
  • the epidermal fraction was carefully lifted with a pincet. By gently scraping the dermis, the adherent keratinocytes were released from the tissue into the trypsin solution. After removal of all dermal parts, the remaining solution (containing the keratinocytes and the stratum corneum sheets) was incubated for 20 min. at 37°C. After filtration, the filter was washed once with keratinocyte-free medium (SFM) and fetal calf serum was added to the filtrate to reach a final concentration of 10% (inactivation of the trypsin-EDTA). After centrifugation of the cell suspension (10 min.
  • SFM keratinocyte-free medium
  • the cells were counted and plated in keratinocyte-SFM (supplemented with an antibiotic-antimycotic mix and 2 ⁇ g gentamycin/ml) at a cell density of 3.10 6 cells/75 cm 2 tissue culture flask and incubated at 37°C in a 5%-CO 2 humidified atmosphere. After 2-3 days of cultivation, the medium was replaced by antibiotic-antimycotic-free medium. After reaching confluence, cells were trypsinized and, after inactivation of the remaining trypsine by fetal calf serum, seeded in 6-well-plates at a cell density of 1.10 5 cells/ml keratinocyte-SFM.
  • the medium was refreshed every 2-3 days and 16 hours before the onset of the experiment.
  • the medium was again replaced by 2 ml of keratinocyte-SFM.
  • the calcitriol metabolism was initiated by adding 0.1 ⁇ Ci 1 ⁇ ,25-[26,27-3H]-dihydroxyvitamin-D 3 in 10 ⁇ l ethanol and 2 ⁇ l drug and/or solvent (DMSO).
  • DMSO drug and/or solvent
  • the medium was transferred into a brown coloured test tube containing 3 ml chloroform and 0.5 ml 10% formic acid.
  • the cells were trypsinized with 0.5 ml trypsine (0.125%) - EDTA (0.01%) and after 15 min.
  • Pig kidney cells collected from one 75 cm 2 tissue culture flask were suspended in 160 ml Medium 199 (a synthetic culture medium supplied by Life-Technologies) containing 3% foetal calf serum (FCS). Two ml of the cell suspension were seeded in 6-well plates and incubated at 37°C in a humidified 5% CO2 atmosphere. The medium was refreshed every 2-3 days. At the onset of the experiment, confluent cultures were washed with phosphate buffer (PBS) without calcium and magnesium and refreshed with with 2 ml medium 199 without serum. The metabolism of l ⁇ ,25-[26,27- 3 H]-dihydroxyvitamin- D 3 was studied as described for the human foreskin keratinocytes.
  • PBS phosphate buffer
  • Human hepatoma cells were grown at 37°C (in a CO 2 incubator) in 2 ml REG A-3 medium (a synthetic culture medium supplied by Life-Technologies) supplemented with 5% FCS. After 24 h of growth, 1.25 ⁇ Ci [ 14 C]-acetate, drug and/or DMSO were added and cells were grown for another 24 h. At the end of the incubation period, cells were collected by centrifugation, washed with physiological saline and resuspended in 1 ml H 2 O and 1 ml 15% KOH in 90% ethanol. The metabolism of 1 ⁇ ,25-[26,27- 3 H]- dihydroxyvitamin-D 3 was studied as described for the human foreskin keratinocytes.
  • IC 50 values for the compounds of formula (I) were calculated by conventional techniques. Table 1 summarizes the obtained IC 50 values for some of the subject compounds.

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Abstract

L'invention se rapporte à l'utilisation d'un (1H-imidazol-1yl)méthyle-1H-benzimidazole, d'un sel d'addition pharmaceutiquement acceptable ou d'une forme stéréochimiquement isomère de celui-ci, ce benzimidazole étant destiné à la fabrication d'un médicament en vue de traiter un état pathologique se trouvant sous l'influence bénéfique de l'inhibition de la dégradation métabolique du calcitriol. Le benzimidazole de l'invention à la formule (I) dans laquelle R représente hydrogène; alkyle en C1-10; cycloalkyle en C3-7; Ar?1 ou Ar1-C¿1-6 alkyle; R1 représente hydrogène; cycloalkyle en C¿3-7; Ar?1; alkyle en C¿1-10?; alkyle en C1-6 substitué par Ar?1¿ ou cycloalkyle en C¿3-7?; hydroxy; alkyloxy en C1-10; alkyloxy en C1-6 substitué par Ar?1¿ ou cycloalkyle en C¿3-7?; alkényloxy en C3-6 éventuellement substitué par Ar?2¿; alkényloxy en C¿3-6? éventuellement substitué par Ar?2; ou Ar1¿- oxy; R2 représente hydrogène; halo; alkyle en C¿1-10?, alkyle C1-4 substitué par au moins 4 atomes halo; cycloalkyle en C3-7; Ar?1¿; quinolinyle; indolinyle; alkyle C¿1-6? substitué par Ar?1¿, cycloalkyle en C¿3-7?; quinolinyle, indolinyle ou hydroxy; alkyloxy en C1-10; alkyloxy en C1-6 substitué par Ar?1¿ ou cycloalkyle en C¿3-7?; alcényle en C3-6 éventuellement substitué par Ar?1; Ar2¿-oxy; alkyloxycarbonyle en C¿1-6?; carboxyle; alkylecarbonyle en C1-6; Ar?1¿-carbonyle ou Ar1-(CHOH)-. Ces compositions comprennent le calcitriol ou un promédicament de celui-ci et un composé de la formule (I).
PCT/EP1995/005172 1994-12-28 1995-12-21 Benzimidazoles utilises comme inhibiteurs du metabolisme du calcitriol WO1996019991A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP95943236A EP0800391A1 (fr) 1994-12-28 1995-12-21 Benzimidazoles utilises comme inhibiteurs du metabolisme du calcitriol
JP8520221A JPH10511653A (ja) 1994-12-28 1995-12-21 カルシトリオール代謝の阻害剤としてのベンゾイミダゾール類
AU44361/96A AU4436196A (en) 1994-12-28 1995-12-21 Benzimidazoles as inhibitors of calcitriol metabolism

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP94203774.8 1994-12-28
EP94203774 1994-12-28

Publications (1)

Publication Number Publication Date
WO1996019991A1 true WO1996019991A1 (fr) 1996-07-04

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PCT/EP1995/005172 WO1996019991A1 (fr) 1994-12-28 1995-12-21 Benzimidazoles utilises comme inhibiteurs du metabolisme du calcitriol

Country Status (4)

Country Link
EP (1) EP0800391A1 (fr)
JP (1) JPH10511653A (fr)
AU (1) AU4436196A (fr)
WO (1) WO1996019991A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999044414A2 (fr) 1998-03-03 1999-09-10 Kristoffer Larsen Innovation A/S Systeme d'elevage d'animaux
US8188131B2 (en) 2008-02-07 2012-05-29 Massachusetts Eye & Ear Infirmary Compounds that enhance Atoh1 expression
US8501770B2 (en) 2009-12-30 2013-08-06 Arqule, Inc. Substituted imidazopyridinyl-aminopyridine compounds
US8609688B2 (en) 2011-06-24 2013-12-17 Arqule, Inc. Substituted imidazopyridinyl-aminopyridine compounds
US8815854B2 (en) 2011-06-24 2014-08-26 Arqule, Inc. Substituted imidazopyridinyl compounds

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EP0371559A2 (fr) * 1988-11-29 1990-06-06 Janssen Pharmaceutica N.V. Utilisation des dérivés du benzimidazoles dans le traitement des troubles épithéliaux
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EP0371559A2 (fr) * 1988-11-29 1990-06-06 Janssen Pharmaceutica N.V. Utilisation des dérivés du benzimidazoles dans le traitement des troubles épithéliaux
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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999044414A2 (fr) 1998-03-03 1999-09-10 Kristoffer Larsen Innovation A/S Systeme d'elevage d'animaux
US8188131B2 (en) 2008-02-07 2012-05-29 Massachusetts Eye & Ear Infirmary Compounds that enhance Atoh1 expression
US8859597B2 (en) 2008-02-07 2014-10-14 Massachusetts Eye & Ear Infirmary Compounds that enhance Atoh1 expression
US9433610B2 (en) 2008-02-07 2016-09-06 Massachusetts Eye & Ear Infirmary Compounds that enhance Atoh1 expression
US10406163B2 (en) 2008-02-07 2019-09-10 Massachusetts Eye & Ear Infirmary Compounds that enhance Atoh1 expression
US11160808B2 (en) 2008-02-07 2021-11-02 Massachusetts Eye & Ear Infirmary Compounds that enhance Atoh1 expression
US8501770B2 (en) 2009-12-30 2013-08-06 Arqule, Inc. Substituted imidazopyridinyl-aminopyridine compounds
US8609688B2 (en) 2011-06-24 2013-12-17 Arqule, Inc. Substituted imidazopyridinyl-aminopyridine compounds
US8815854B2 (en) 2011-06-24 2014-08-26 Arqule, Inc. Substituted imidazopyridinyl compounds
US8962619B2 (en) 2011-06-24 2015-02-24 Arqule, Inc. Substituted imidazopyridinyl-aminopyridine compounds

Also Published As

Publication number Publication date
AU4436196A (en) 1996-07-19
EP0800391A1 (fr) 1997-10-15
JPH10511653A (ja) 1998-11-10

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