WO1998022108A1 - Imidazoles a substitution triaryle et leurs procedes d'utilisation - Google Patents

Imidazoles a substitution triaryle et leurs procedes d'utilisation Download PDF

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Publication number
WO1998022108A1
WO1998022108A1 PCT/US1997/020955 US9720955W WO9822108A1 WO 1998022108 A1 WO1998022108 A1 WO 1998022108A1 US 9720955 W US9720955 W US 9720955W WO 9822108 A1 WO9822108 A1 WO 9822108A1
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Prior art keywords
pyridyl
imidazole
fluorophenyl
chlorophenyl
alkyl
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PCT/US1997/020955
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English (en)
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Linda L. Chang
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Merck & Co., Inc.
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Priority claimed from GBGB9700559.9A external-priority patent/GB9700559D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU54414/98A priority Critical patent/AU726311B2/en
Priority to CA002271941A priority patent/CA2271941A1/fr
Priority to JP52378498A priority patent/JP2001504489A/ja
Priority to EP97948327A priority patent/EP0959885A4/fr
Publication of WO1998022108A1 publication Critical patent/WO1998022108A1/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
    • A61K31/435—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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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 relates to triaryl substituted imidazoles which antagonize the metabolic effect of glucagon.
  • Diabetes is a disease process derived from multiple causative factors and characterized by elevated levels of plasma glucose. Uncontrolled hyperglycemia is associated with an increased risk for microvascular and macrovascular diseases, including nephropathy, retinopathy, hypertension, stroke and heart disease. Control of glucose homeostasis is, therefore, a major approach to the treatment of diabetes.
  • Glucagon is a major counter regulatory hormone that attenuates the inhibition of liver gluconeogenesis by insulin.
  • Glucagon receptors are found primarily in the liver, although their presence has been documented in kidney, pancreas, adipose tissues, heart, smooth muscles of vascular tissues, and some regions of the brain, stomach and adrenal glands.
  • Type II diabetics have elevated levels of plasma glucagon and increased rates of hepatic glucose production.
  • the rate of hepatic glucose production positively correlates with fasting blood glucose levels in type II diabetics. Therefore, antagonists of glucagon are useful in improving insulin responsiveness in the liver, decreasing the rate of gluconeogenesis and lowering the rate of hepatic glucose output resulting in a decrease in the levels of plasma glucose.
  • Glu-mAb A monoclonal antibody to glucagon (Glu-mAb) has been utilized to test the acute effects of attenuation of glucagon action in streptozotocin-treated diabetic rats (Brand et al., Diabetologia 37:985, 1994).
  • injection of Glu-mAb attenuated the postprandial increase in blood glucose in moderately hyperglycemic rats (ie., rats with a moderate impairment in insulin secretion).
  • Glu-mAb injection did not lower blood glucose levels, but potentiated the hypoglycemic effect of a suboptimal dose of insulin.
  • glucagon homeostasis is also mediated by the hormone insulin, produced in the ⁇ cells of the pancreas. Deterioration of these cells is typically observed in Type I diabetics, and abnormalities in the function of these cells may occur in patients presenting the symptoms of Type II diabetes. Thus, a glucagon antagonist might have utility in treating Type I diabetics.
  • the glucagon receptor is expressed in kidney tissues where glucagon has been demonstrated to have an effect on electrolyte homeostasis including the ions sodium, potassium, chloride, magnesium, calcium, and phosphate and the non-electrolytes urea and water (Ahloulay et al., Am. J. PhysioL, 269: F225, 1995).
  • a glucagon antagonist may have use in treating disorders involving electrolyte imbalance.
  • the kidney is also gluconeogenic in response to glucagon (Amores et al., Molec. Cell. Biochem., 137: 117, 1994) and an antagonist would act to lower glucose production in kidney furthering the treatment of diabetes.
  • Glucagon receptors are present in the heart and in smooth muscles. Glucagon has a direct effect on cardiac output and heart rate (Glick et al., Circ. Res., 22: 789 (1968); Farah, Pharm. Rev., 35: 181, 1983). A strong correlation has been observed in patients with hypertension and elevated plasma glucagon levels resulting from impaired hepatic catabolism (Silva et al., Heptatology, 11: 668, 1990). Antagonism of the effects of elevelated glucagon levels may have an effect on certain types of hypertension, thus a glucagon antagonist may have utility in the treatment of certain types of hypertension associated with elevated glucagon production.
  • glucagon and glucagon receptors associated with adipose tissues The primary role for glucagon and glucagon receptors associated with adipose tissues is to induce lipolysis, thus providing free fatty acids as a substrate for fat burning tissues (Saggerson et al.,
  • glucagon and glucagon receptors have been localized to the hippocampus region of the brain (Hoosein and Gurd, Proc. Natl. Acad. Sci. USA, 81: 4368, 1984). This discovery suggests that glucagon may have a neuroendocrine role in initiating or elaborating basic behavior or somatic motor programs. Since glucagon secretion is increased in response to low blood glucose levels, increased glucagon levels in the brain may initiate behavior to respond to low glucose levels, such as eating. Thus, chronic hyperglucagonemia may also result in a constant craving for food resulting in obesity. A glucagon antagonist may have utility in treating obesity by altering feeding behavior associated with a response to glucagon.
  • the compounds in the present invention are glucagon antagonists.
  • the compounds block the action of glucagon at its receptors and thereby decrease the levels of plasma glucose.
  • the instant compounds thus are useful as antidiabetic agents.
  • Glucagon may have other direct effects on cardiac output, lipolysis, and feeding behavior and therefore may be useful as antihypertensive, anti-cachexia or antiobesity agents.
  • the present invention relates to 2,4-diaryl-5-pyridyl imidazoles which are glucagon receptor antagonists. These compounds are therefore useful for the treatment of diseases caused by excessive levels of glucagon, including diabetes and certain types of hypertension, cachexia and obesity. Also included in the invention are pharmaceutical compositions which comprise a compound of formula I in combination with a pharmaceutically acceptable carrier.
  • the present invention provides a method of treating glucagon-mediated diseases, in a mammal in need of such treatment, which comprises administering to said mammal an effective amount of a glucagon antagonist of formula (I):
  • Rl is 4-pyridyl, 4-pyrimidinyl or 4-quinolyl which is unsubstituted or substituted with one or two substituents each of which is independently selected from the group consisting of
  • Ci-io alkyl- wherein said alkyl is optionally substituted with from 1 to 5 halogen atoms, (4) -O-Ci-i ⁇ alkyl,
  • R2 is phenyl, 1-naphthyl, 2-naphthyl or heteroaryl which is unsubstituted or substituted with one, two or three substituents each of which is independently selected from the group consisting of (1) Cl-10 alkyl, (2) R4, and
  • R3 is phenyl, 1-naphthyl, or 2-naphthyl which is unsubstituted or substituted with up to fivesubstituents each of which is independently selected from the group consisting of
  • R7 and R17 are each independently selected from hydrogen or C ⁇ -4 alkyl or
  • R7 and R17 together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR22;
  • R8 and R9 are independently selected from
  • R8 and R9 together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR12;
  • RlO and R20 is each independently selected from hydrogen or Cl-4 alkyl;
  • Rl l is (1) Cl-10 alkyl
  • Rl2 is (1) hydrogen
  • Rl3 is (1) hydrogen, or
  • R]4 and R24 is each independently selected from
  • Rl5 is (1) hydrogen
  • Rl 8 and R19 is each independently selected from
  • Rl 8 and R19 together denote an oxo or thioxo
  • R21 is (1) Rl3,
  • R22 ⁇ S RlO or C(Z)-C 1-4 alkyl
  • R25 is (1) Cl-10 alkyl
  • Z is oxyg ⁇ en or sulfur; m is 1 or 2; n is 1 to 10; p is 1 to 10; or a pharmaceutically acceptable salt thereof.
  • the compounds of formula I are those wherein
  • Rl is 4- -pyridyl which is unsubstituted or substituted with one or two substituents each of which is independently selected from the group consisting of
  • the compounds of formula I are those wherein R2 is phenyl, 1-naphthyl, 2-naphthyl or thienyl which is unsubstituted or substituted with one or two substituents each of which is independently selected from the group consisting of
  • R3 is phenyl, 1-naphthyl, or 2-naphthyl which is unsubstituted or substituted with up to five substituents each of which is independently selected from the group consisting of
  • Cl_3alkyl wherein said alkyl is optionally substituted with from 1 to 5 halogen atoms
  • Rl is 4-pyridyl unsubstituted or substituted with one or two substituents each of which is independently selected from the group consisting of (1) Ci-io alkyl, wherein said alkyl is optionally substituted with from 1 to 5 halogen atoms,
  • R2 is phenyl, 1-naphthyl, 2-naphthyl or thienyl which is unsubstituted or substituted with one or two substituents each of which is independently selected from the group consisting of (1) Cl-10 alkyl,
  • R3 is phenyl, 1-naphthyl, or 2-naphthyl which is unsubstituted or substituted with up to five substituents each of which is independently selected from the group consisting of
  • Halogen includes fluorine, chlorine, bromine and iodine.
  • alkyl refers to a monovalent alkane (hydrocarbon)-derived radical containing the designated number of carbon atoms. It may be straight or branched. Examples include methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, sec-butyl, isopentyl and t- butyl.
  • cycloalkyl refers to a cyclized alkane (hydrocarbon)-derived radical containing the designated number of carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • alkenyl refers to a hydrocarbon radical, straight or branched, containing the designated number of carbon atoms and at least one carbon to carbon double bond. Preferably one carbon to carbon double bond is present, and up to four non-aromatic (non-resonating) carbon-carbon double bonds may be present. Examples of alkenyl groups include ethenyl, propenyl, butenyl and isobutenyl.
  • alkynyl refers to a hydrocarbon radical, straight or branched, containing the designated number of carbon atoms and at least one carbon to carbon triple bond. Up to three carbon-carbon triple bonds may be present. Examples of alkynyl groups include ethynyl, propynyl and butynyl.
  • Aryl refers to aromatic rings including phenyl and naphthyl.
  • heteroaryl (on its own or in any combination, such as “heteroaryloxy”) represents a 5-10 membered aromatic ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O and S, such as, but not limited to pyridyl, pyrimidinyl, pyrrolyl, furyl, thienyl, imidazolyl, thiazolyl, thiadiazolyl, tetrazolyl, triazolyl, oxadiazolyl, oxazolyl, imidazolidinyl, pyrazolyl, isoxazolyl, benzothiadiazolyl, indolyl, indolinyl, benzodioxolyl, benzodioxanyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazin
  • heterocyclylalkyl represents a saturated or wholly or partially unsaturated 4-10 membered ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O and S.
  • heterocyclyls are piperidinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydroimidazo[4,5-c]pyridine, imidazolinyl, piperazinyl, pyrazolindinyl and the like.
  • composition as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
  • the compounds of the present invention may contain one or more asymmetric carbon atoms and may occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included within the scope of the present invention.
  • the pharmaceutically acceptable salts of the compounds of formula I include the conventional non-toxic salts or the quaternary ammonium salts of the compounds of formula I formed e.g. from non- toxic inorganic or organic acids.
  • such conventional non- toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of formula I which contain a basic or acidic moiety by conventional chemical methods. Generally, the salts are prepared by reacting the free base or acid with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid or base in a suitable solvent or various combinations of solvents.
  • This invention relates to a method of inhibiting the action of glucagon at its receptors thereby reducing the rate of gluconeogenesis and the concentration of glucose in plasma.
  • compounds of formula I can be used in the prophylaxis or treatment of disease states in mammals mediated by elevated levels of glucagon. Examples of such disease states include diabetes, obesity, hypertension, and cachexia and the like.
  • the compounds of formula I are normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • This invention also relates to a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier or diluent.
  • the pharmaceutical carrier employed may be, for example, solid or liquid.
  • Solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
  • Liquid carriers include syrup, peanut oil, olive oil, water and the like.
  • the carrier may include time delay material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • the compounds of formula I are administered in conventional dosage forms prepared by combining a compound of formula I with standard pharmaceutical carriers according to conventional procedures.
  • the compounds of formula I may also be administered in conventional dosages in combination with a known, second therapeutically active compound. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
  • the active compounds of the present invention may be orally administered as a pharmaceutical composition, for example, with an inert diluent, or with an assimilable edible carrier, or they may be enclosed in hard or soft shell capsules, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet.
  • these active compounds may be incorporated with excipients and used in the form of tablets, pills, capsules, ampules, sachets, elixirs, suspensions, syrups, and the like.
  • Such compositions and preparations should contain at least 0.1 percent of active compound.
  • the percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained.
  • the tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin.
  • a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
  • tablets may be coated with shellac, sugar or both.
  • a syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
  • active compounds may also be administered parenterally, for example intravenously, intramuscularly, intradermally or subcutaneously.
  • Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxy- propylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
  • the compounds of formula I may also be administered topically in the form of a liquid, solid or semi- solid.
  • Liquids include solutions, suspensions and emulsions.
  • Solids include powders, poultices and the like.
  • Semi-solids include creams, ointments, gels and the like.
  • Drops according to the present invention may comprise sterile aqueous or oil solutions or suspensions, and may be prepared by dissolving the active ingredient in a suitable aqueous solution, optionally including a bactericidal and/or fungicidal agent and/or any other suitable preservative, and optionally including a surface active agent.
  • Lotions according to the present invention include those suitable for application to the skin or eye.
  • An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation of drops.
  • Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a moisturizer such as glycerol or an oil such as castor oil or arachis oil.
  • Creams, ointments or pastes according to the present invention are semi- solid formulations of the active ingredient for external application. They may be made by mixing the active ingredient in finely- divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous liquid, with the aid of suitable machinery, with a greasy or non-greasy base.
  • the base may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, corn, arachis, castor or olive oil; wool fat or its derivatives, or a fatty acid such as steric or oleic acid together with an alcohol such as propylene glycol or macrogels.
  • the formulation may incorporate any suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as sorbitan esters or polyoxyethylene derivatives thereof.
  • Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicas, and other ingredients such as lanolin may also be included.
  • Compounds of the present invention may also be administered intranasally as, for example, liquid drops or spray; by intranasal or oral inhalation; rectally; trasdermally; or vaginally.
  • a representative dosing regimen for treating diabetes mellitus and/or hyperglycemia may involve administering a compound of formula I at a daily dosage of from about 0.001 milligram to about 100 milligram per kilogram of animal body weight, preferably given in a single dose or in divided doses two to six times a day, or in sustained release form. In the case of a 70 kg adult human, the total daily dose will generally be from about 0.07 milligrams to about 350 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
  • Compounds of the present invention may be prepared by several general synthetic methods as described in, for example, M. R. Grimmett, Comprehensive Heterocyclic Chemistry, The Structure, Reactions, Synthesis and Uses of Heterocyclic Compounds, A. R. Katritzky and C. W. Rees, eds., Vol. 5, Pergamon Press, Oxford, 1984, pp. 457-498.
  • the compounds of the present invention can be prepared by procedures illustrated in the accompanying schemes.
  • the three general methods for preparation of the imidazole nucleus are outlined in Schemes 1 and 2.
  • an heteroarylmethane (6) (e.g., when Rl is 4-pyridyl, (6) is 4-picoline) is deprotonated with a strong base such as lithium diisopropyl amide or n-butyl lithium and the resulting anion is reacted with N,0-dimethylhydroxamide (2) to give a ketone (7).
  • the dione (8) is obtained by selenium dioxide oxidation of the ketone (7) and then condensed with a suitably functionalized aldehyde (4) in the presence of ammonium acetate in acetic acid to form the desired imidazole (5).
  • Step A 4-t-Butydimethylsilyloxymethylpyridine
  • 4-pyridylcarbinol 50.3 g, 0.46 mol
  • methylene chloride 250 mL
  • triethylamine 97 mL, 0.69 mol
  • T 34 C cooling
  • the reaction mixture was stirred overnight at room temperature.
  • the slurry was then filtered and the solvent removed by rotoevaporation.
  • the residue was suspended in toluene and filtered and the solvent removed by rotoevaporation.
  • the residue was suspended in diethyl ether and filtered and the solvent removed by rotoevaporation.
  • the same process was repeated with hexanes to yield 4-t-butydimethylsilyloxymethylpyridine as a brown oil.
  • Step C 4-Pyridyl-t-butydimethylsilyloxymethyl 4-fluorophenyl ketone
  • Step D 2-(4-Bromophenyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole
  • acetic acid 2 mL
  • copper(II) acetate 105.1 mg, 0.58 mmol
  • solid ammonium acetate 222 mg, 2.89 mmol
  • 4-bromobenzaldehyde 66.8 mg
  • Step A 3-Bromo-N-methoxy-N-methylbenzamide.
  • Step B ' 3-Bromophenyl 4-pyridy lmethyl ketone
  • the reaction mixture was stirred for 1 h with gradual warming to -30 C.
  • the reaction was then quenched with saturated ammonium chloride solution (5 mL).
  • the phases were separated and the aqueous layer was extracted with ethyl acetate (2 times).
  • the combined organic phases were washed successively with water and saturated salt solution and dried over anhydrous sodium sulfate.
  • the solvent was removed by rotoevaporation and the crude product purified by flash column chromatography on silica gel eluted with 0-50% ethyl acetate in hexanes.
  • Step C 1 -(3-BromophenylV 2-(4-pyridyl - ethane- 1.2-dione
  • Step D 4-(3-Bromophenyl -2-(4-chlorophenyl -5-(4-pyridyl)imidazole
  • Step B 3-Iodophenyl 4-pyridylmethyl ketone
  • the stirred reaction mixture was allowed to warm to 5 °C over 4 h.
  • the reaction was quenched by the addition of a 1/2 saturated solution of ammonium chloride (30 mL) at 0 to 5 °C.
  • the phases were separated and the aqueous phase extracted with ethyl acetate (3 times).
  • the combined organic layers were successively washed with water and saturated salt solution and dried over anhydrous sodium sulfate.
  • Step C 1 -(3-Iodophenyl)-2-(4-pyridy ethane- 1.2-dione
  • a mixture of 3-iodophenyl 4-pyridylmethyl ketone from Step B (3.09 g, 9.57 mmol) and selenium dioxide powder (1.062 g, 9.57 mmol) in degassed glacial acetic acid (22 mL) was heated to 90 °C for 30 min in the dark.
  • the reaction mixture was cooled to 0 °C and ethyl acetate (30 mL) was added.
  • a solution of potassium carbonate (26 g) in water (140 mL) was carefully added dropwise to the reaction mixture until the pH reached ⁇ 8.
  • Step D 2-(4-Azidophenyl)-4-(3-iodophenyl)-5-(4-pyridyl)imidazole [Note: It is important to perform this reaction and all subsequent manipulations including drying, rotoevaporation and column chromatography as much in the dark as possible.
  • the aqueous phase (adjusted to pH 10 with more ammonium hydroxide solution) was extracted with ethyl acetate (3 times).
  • the combined organic layers were washed successively with water and saturated salt solution and dried over anhydrous sodium sulfate.
  • the solvent was removed by rotoevaporation and the residue purified by flash column chromatography on silica gel eluted with 25-80% ethyl acetate in hexanes to yield the title compound as a pale brown glass (579 mg, 33% yield), mass spectrum (Cl) m/e 465.1 (M+l)+.
  • BIOLOGICAL ASSAYS The ability of compounds of the present invention to inhibit the binding of glucagon and the synthesis or the activity of cytokines can be determined by the following in vitro assays.
  • 125i-Glucagon Binding Screen with CHO/hGLUR Cells The reagents are prepared as follows:
  • Assay Buffer 20 mM Tris, pH 7.8; 1 mM DTT; 3 mM o- phenanthroline.
  • Assay Buffer w/ 0.1% BSA for dilution of label only, therefore 0.01% final in assay: 10 ⁇ l 10% BSA (heat-inactivated) + 990 ⁇ l assay buffer
  • 125l-Glucagon (NEN #NEX-207, receptor-grade, 2200 Ci/mmol): Dilute to 50,000 cpm/25 ⁇ l in assay buffer w/ BSA.Thus, -50 pM final concentration in assay.
  • membrane preparations from CHO/hGLUR cells can be used in place of whole cells at the same assay volume. Final protein concentration of membrane preparation is determined on a per batch basis.
  • the determination of inhibition of glucagon binding is carried out by measuring the reduction of ll2 .gl U cagon binding in the presence of compounds of Formula I.
  • the assay is carried out in a 96-well box. The following reagents are combined:
  • the box is incubated for 60 min. at 22 Con a shaker at 275 rpm.
  • the wells are filtered over pre-soaked (0.5% polyethylimine(PEI)) GF/C filtermat using an Innotech Harvester or Tomtec Harvester with four washes of ice-cold 20 mM Tris, pH 7.8 buffer. Count filters in Gamma- scintillation counter.

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Abstract

L'invention concerne des 2,4-Diaryl-5-pyridylimidazoles qui constituent des antagonistes de glucagon. Ces composés bloquent l'action du glucagon sur son récepteur. Ainsi, ces composés peuvent s'utiliser dans la prophylaxie ou le traitement d'affections chez les mammifères se manifestant par des taux élevés de glucagon. Le diabète, l'obésité, l'hypertension, la cachexie et d'autres affections similaires constituent des exemples de telles affections.
PCT/US1997/020955 1996-11-20 1997-11-17 Imidazoles a substitution triaryle et leurs procedes d'utilisation WO1998022108A1 (fr)

Priority Applications (4)

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AU54414/98A AU726311B2 (en) 1996-11-20 1997-11-17 Triaryl substituted imidazoles and methods of use
CA002271941A CA2271941A1 (fr) 1996-11-20 1997-11-17 Imidazoles a substitution triaryle et leurs procedes d'utilisation
JP52378498A JP2001504489A (ja) 1996-11-20 1997-11-17 トリアリール置換イミダゾール及び使用方法
EP97948327A EP0959885A4 (fr) 1996-11-20 1997-11-17 Imidazoles a substitution triaryle et leurs procedes d'utilisation

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US3146896P 1996-11-20 1996-11-20
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GBGB9700559.9A GB9700559D0 (en) 1997-01-13 1997-01-13 Triaryl substituted imidazoles and methods of use
GB9700559.9 1997-01-13

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Cited By (29)

* Cited by examiner, † Cited by third party
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US6503949B1 (en) 1999-05-17 2003-01-07 Noro Nordisk A/S Glucagon antagonists/inverse agonists
WO2003024447A1 (fr) * 2001-09-20 2003-03-27 Smithkline Beecham Corporation Inhibiteurs de glycogene synthase kinase-3
WO2003037332A1 (fr) * 2001-10-12 2003-05-08 Bayer Pharmaceuticals Corporation Heterocycles utiles pour le traitement de l'obesite
US6562807B2 (en) 2000-06-23 2003-05-13 Novo Nordisk A/S Glucagon antagonists/inverse agonists
US6649641B2 (en) 1970-11-01 2003-11-18 Novo Nordisk A/S Glucagon antagonists/inverse agonists
US6706744B2 (en) 2000-11-17 2004-03-16 Novo Nordisk A/S Glucagon antagonists/inverse agonists
US6762318B2 (en) 2001-12-03 2004-07-13 Novo Nordisk A/S Glucagon antagonists
WO2004058727A1 (fr) * 2002-12-20 2004-07-15 Bayer Pharmaceuticals Corporation 3,5-dihydro-4-h-imidazol-4-ones substitues utilises dans le traitement de l'obesite
US6821960B2 (en) 2000-11-17 2004-11-23 Noyo Nordisk Pharmaceuticals, Inc. Glucagon antagonists/inverse agonists
US6881746B2 (en) 2001-12-03 2005-04-19 Novo Nordick A/S Glucagon antagonists/inverse agonists
EP1741446A2 (fr) 2000-01-21 2007-01-10 Novartis AG Combinaisons à base d'inhibiteurs de DPP-IV et d'antidiabetiques
WO2007033266A2 (fr) 2005-09-14 2007-03-22 Takeda Pharmaceutical Company Limited Administration d'inhibiteurs de dipeptidyl peptidase
US7301036B2 (en) 2003-12-19 2007-11-27 Merck & Co., Inc. Cyclic guanidines, compositions containing such compounds and methods of use
US7572922B2 (en) 2003-01-27 2009-08-11 Merck & Co., Inc. Substituted pyrazoles, compositions containing such compounds and methods of use
US7598398B2 (en) 2005-10-13 2009-10-06 Merck & Co., Inc. Acyl indoles, compositions containing such compounds and methods of use
US7598285B2 (en) 2004-06-04 2009-10-06 Merck & Co., Inc Pyrazole derivatives, compositions containing such compounds and methods of use
US7625938B2 (en) 2004-07-22 2009-12-01 Merck & Co., Inc. Substituted pyrazoles, compositions containing such compounds and methods of use
US7649009B2 (en) 2004-07-07 2010-01-19 Merck & Co., Inc. Pyrazole amide derivatives, compositions containing such compounds and methods of use
US7687534B2 (en) 2006-10-03 2010-03-30 Merck Sharp & Dohme Corp. Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use
US7709658B2 (en) 2005-07-26 2010-05-04 Merck Sharp & Dohme Corp. Process for synthesizing a substituted pyrazole
US7803951B2 (en) 2005-03-30 2010-09-28 Merck Sharp & Dohme Corp. Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use
WO2011041293A1 (fr) 2009-09-30 2011-04-07 Takeda Pharmaceutical Company Limited Dérivés pyrazolo [1, 5—a] pyrimidines comme inhibiteurs de kinase 1 régulatrice de signal d'apoptose
US7935713B2 (en) 2006-05-16 2011-05-03 Merck Sharp & Dohme Corp. Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use
US7989472B2 (en) 2006-03-23 2011-08-02 Merck Sharp & Dohme Corp. Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use
WO2011097079A1 (fr) 2010-02-03 2011-08-11 Takeda Pharmaceutical Company Limited Inhibiteurs de kinase 1 régulant le signal d'apoptose
US8318760B2 (en) 2005-03-21 2012-11-27 Merck Sharp & Dohme Corp. Substituted aryl and heteroaryl derivatives, compositions containing such compounds and methods of use
WO2015119579A1 (fr) * 2014-02-07 2015-08-13 Agency For Science, Technology And Research Inhibiteurs de la caséine kinase 1 à base d'azole 2,4,5-tri-substitué en tant qu'inducteurs de la cardiomyogenèse
WO2016141381A3 (fr) * 2015-03-05 2016-11-03 University Of Notre Dame Du Lac Potentialisateurs d'antibiotiques bêta-lactames
US9649294B2 (en) 2013-11-04 2017-05-16 Merck Sharp & Dohme Corp. Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use

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US11958828B1 (en) 2023-11-07 2024-04-16 King Faisal University 4,5-bis(4-bromophenyl)-1-hexyl-2-(3-pyridyl)-1H-imidazole as an antimicrobial compound
US11993575B1 (en) 2023-12-29 2024-05-28 King Faisal University Ethyl [4,4-bis(4-bromophenyl)-2,5-dioxoimidazolidin-1-yl]acetate as an antimicrobial compound
US11970462B1 (en) 2024-01-03 2024-04-30 King Faisal University Ethyl 3-[4,4-bis(4-chlorophenyl)-2,5-dioxoimidazolidin-1-yl]propanoate as an antimicrobial compound

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US5620999A (en) * 1994-07-28 1997-04-15 Weier; Richard M. Benzenesulfonamide subtituted imidazolyl compounds for the treatment of inflammation

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Cited By (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6649641B2 (en) 1970-11-01 2003-11-18 Novo Nordisk A/S Glucagon antagonists/inverse agonists
US6503949B1 (en) 1999-05-17 2003-01-07 Noro Nordisk A/S Glucagon antagonists/inverse agonists
US6875760B2 (en) 1999-05-17 2005-04-05 Novo Nordisk A/S Glucagon antagonists/inverse agonists
EP1741446A2 (fr) 2000-01-21 2007-01-10 Novartis AG Combinaisons à base d'inhibiteurs de DPP-IV et d'antidiabetiques
EP1743655A1 (fr) 2000-01-21 2007-01-17 Novartis AG Combinaisons à base d'inhibiteurs de DPP-IV et d'antidiabétiques
US6953812B2 (en) 2000-06-23 2005-10-11 Novo Nordisk, Inc. Glucagon antagonists/inverse agonists
US6562807B2 (en) 2000-06-23 2003-05-13 Novo Nordisk A/S Glucagon antagonists/inverse agonists
US6706744B2 (en) 2000-11-17 2004-03-16 Novo Nordisk A/S Glucagon antagonists/inverse agonists
US6821960B2 (en) 2000-11-17 2004-11-23 Noyo Nordisk Pharmaceuticals, Inc. Glucagon antagonists/inverse agonists
WO2003024447A1 (fr) * 2001-09-20 2003-03-27 Smithkline Beecham Corporation Inhibiteurs de glycogene synthase kinase-3
WO2003037332A1 (fr) * 2001-10-12 2003-05-08 Bayer Pharmaceuticals Corporation Heterocycles utiles pour le traitement de l'obesite
US6881746B2 (en) 2001-12-03 2005-04-19 Novo Nordick A/S Glucagon antagonists/inverse agonists
US6762318B2 (en) 2001-12-03 2004-07-13 Novo Nordisk A/S Glucagon antagonists
WO2004058727A1 (fr) * 2002-12-20 2004-07-15 Bayer Pharmaceuticals Corporation 3,5-dihydro-4-h-imidazol-4-ones substitues utilises dans le traitement de l'obesite
US7989475B2 (en) 2003-01-27 2011-08-02 Merck Sharp & Dohme Corp. Substituted pyrazoles, compositions containing such compounds and methods of use
US7572922B2 (en) 2003-01-27 2009-08-11 Merck & Co., Inc. Substituted pyrazoles, compositions containing such compounds and methods of use
US7301036B2 (en) 2003-12-19 2007-11-27 Merck & Co., Inc. Cyclic guanidines, compositions containing such compounds and methods of use
US7598285B2 (en) 2004-06-04 2009-10-06 Merck & Co., Inc Pyrazole derivatives, compositions containing such compounds and methods of use
US7799818B2 (en) 2004-06-04 2010-09-21 Merck Sharp & Dohme Corp. Pyrazole derivatives, compositions containing such compounds and methods of use
US7649009B2 (en) 2004-07-07 2010-01-19 Merck & Co., Inc. Pyrazole amide derivatives, compositions containing such compounds and methods of use
US7625938B2 (en) 2004-07-22 2009-12-01 Merck & Co., Inc. Substituted pyrazoles, compositions containing such compounds and methods of use
US8318760B2 (en) 2005-03-21 2012-11-27 Merck Sharp & Dohme Corp. Substituted aryl and heteroaryl derivatives, compositions containing such compounds and methods of use
US7803951B2 (en) 2005-03-30 2010-09-28 Merck Sharp & Dohme Corp. Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use
US7709658B2 (en) 2005-07-26 2010-05-04 Merck Sharp & Dohme Corp. Process for synthesizing a substituted pyrazole
WO2007033266A2 (fr) 2005-09-14 2007-03-22 Takeda Pharmaceutical Company Limited Administration d'inhibiteurs de dipeptidyl peptidase
US7598398B2 (en) 2005-10-13 2009-10-06 Merck & Co., Inc. Acyl indoles, compositions containing such compounds and methods of use
US7989472B2 (en) 2006-03-23 2011-08-02 Merck Sharp & Dohme Corp. Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use
US7935713B2 (en) 2006-05-16 2011-05-03 Merck Sharp & Dohme Corp. Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use
US7968589B2 (en) 2006-10-03 2011-06-28 Merck Sharp & Dohme Corp. Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use
US7687534B2 (en) 2006-10-03 2010-03-30 Merck Sharp & Dohme Corp. Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use
WO2011041293A1 (fr) 2009-09-30 2011-04-07 Takeda Pharmaceutical Company Limited Dérivés pyrazolo [1, 5—a] pyrimidines comme inhibiteurs de kinase 1 régulatrice de signal d'apoptose
WO2011097079A1 (fr) 2010-02-03 2011-08-11 Takeda Pharmaceutical Company Limited Inhibiteurs de kinase 1 régulant le signal d'apoptose
US9649294B2 (en) 2013-11-04 2017-05-16 Merck Sharp & Dohme Corp. Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use
WO2015119579A1 (fr) * 2014-02-07 2015-08-13 Agency For Science, Technology And Research Inhibiteurs de la caséine kinase 1 à base d'azole 2,4,5-tri-substitué en tant qu'inducteurs de la cardiomyogenèse
US10865384B2 (en) 2014-02-07 2020-12-15 Agency For Science, Technology And Research 2,4,5-tri-substituted azole-based casein kinase 1 inhibitors as inducers for cardiomyogenesis
WO2016141381A3 (fr) * 2015-03-05 2016-11-03 University Of Notre Dame Du Lac Potentialisateurs d'antibiotiques bêta-lactames

Also Published As

Publication number Publication date
EP0959885A4 (fr) 2002-07-17
AU726311B2 (en) 2000-11-02
CA2271941A1 (fr) 1998-05-28
JP2001504489A (ja) 2001-04-03
EP0959885A1 (fr) 1999-12-01
AU5441498A (en) 1998-06-10

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