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WO2011027849A1 - Composé hétérocyclique - Google Patents

Composé hétérocyclique Download PDF

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Publication number
WO2011027849A1
WO2011027849A1 PCT/JP2010/065102 JP2010065102W WO2011027849A1 WO 2011027849 A1 WO2011027849 A1 WO 2011027849A1 JP 2010065102 W JP2010065102 W JP 2010065102W WO 2011027849 A1 WO2011027849 A1 WO 2011027849A1
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WO
WIPO (PCT)
Prior art keywords
methyl
amino
pyridin
chloro
compound
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PCT/JP2010/065102
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English (en)
Japanese (ja)
Inventor
能紀 余郷
亮磨 原
耕一朗 福田
Original Assignee
武田薬品工業株式会社
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Publication of WO2011027849A1 publication Critical patent/WO2011027849A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to a heterocyclic compound having glucagon antagonism useful for prevention or treatment of diabetes and the like.
  • Glucagon is a linear peptide hormone consisting of 29 amino acids secreted from pancreatic alpha cells, and promotes glycogenolysis and gluconeogenesis in the liver. In diabetic patients, glucagon secretion and reactivity are generally increased, which contributes to hyperglycemia. Therefore, the glucagon receptor antagonist can suppress the excessive sugar production from the liver by blocking the action of glucagon, and is useful as a therapeutic agent for diabetes.
  • Patent Document 1 As glucagon antagonists, compounds described in International Publication 2009/057784 (Patent Document 1) and International Publication 2009/110520 (Patent Document 2) are known.
  • compound (I) glucagon antagonism. And has an excellent medicinal effect as a preventive or therapeutic agent for diabetes and the like. Based on this knowledge, the present inventors have conducted intensive studies and completed the present invention.
  • the present invention (1) 3- ⁇ [(6- ⁇ [(5-Chloro-1-methyl-1H-indol-2-yl) (cyclohexyl) methyl] amino ⁇ pyridin-3-yl) carbonyl] (methyl) amino ⁇ propane Acid or salt thereof; (2) 3- ⁇ [(6- ⁇ [cyclohexyl (5-fluoro-1-methyl-1H-indol-2-yl) methyl] amino ⁇ pyridin-3-yl) carbonyl] (methyl) amino ⁇ propanoic acid or Its salt; (3) 3- ⁇ [(6- ⁇ [(5-Chloro-1-methyl-1H-indol-2-yl) (cyclopentyl) methyl] amino ⁇ pyridin-3-yl) carbonyl] (methyl) amino ⁇ propane Acid or salt thereof; (4) 3- ⁇ [(4- ⁇ [(5-Chloro-3-methylthieno [2,3-c] pyridin-2-yl) (cyclohexyl) methyl]
  • the compound of the present invention has a glucagon antagonism and an excellent drug effect (suppression of blood sugar, action of lowering blood sugar, etc.), and thus is useful for prevention or treatment of diabetes and the like.
  • the salt in compound (I) is preferably a pharmacologically acceptable salt.
  • a salt with an inorganic base examples include a salt with an organic base, a salt with an inorganic acid, and an organic acid. And salts with basic or acidic amino acids.
  • the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; aluminum salt; ammonium salt and the like.
  • the salt with an organic base include trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris (hydroxymethyl) methylamine], tert-butylamine, cyclohexylamine, benzylamine, And salts with dicyclohexylamine, N, N-dibenzylethylenediamine and the like.
  • salt with inorganic acid examples include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, and benzenesulfonic acid And salts with p-toluenesulfonic acid and the like.
  • salts with basic amino acids include salts with arginine, lysine, ornithine and the like.
  • salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like.
  • Compound (I) can be produced according to a method known per se or a method analogous thereto, for example, the method described in the Examples below.
  • compound (I) When compound (I) is obtained as a free compound, it can be converted to the target salt by a method known per se or a method analogous thereto, and conversely when it is obtained as a salt, it is known per se. It can be converted into a free form or other desired salt by the method of or similar thereto.
  • Compound (I) includes optically active forms such as racemates, R-forms and S-forms. Specific examples of such optical isomers of compound (I) are shown below: (1) 3- ⁇ [(6- ⁇ [(5-Chloro-1-methyl-1H-indol-2-yl) (cyclohexyl) methyl] amino ⁇ pyridin-3-yl) carbonyl] (methyl) amino ⁇ propane As an optical isomer of acid, 3- ⁇ [(6- ⁇ [(R)-(5-Chloro-1-methyl-1H-indol-2-yl) (cyclohexyl) methyl] amino ⁇ pyridin-3-yl) carbonyl] (methyl) amino ⁇ Propanoic acid, and 3- ⁇ [(6- ⁇ [(S)-(5-Chloro-1-methyl-1H-indol-2-yl) (cyclohexyl) methyl] amino ⁇ pyridin-3-yl) carbonyl] (methyl) amino ⁇ And propanoic acid
  • the optical isomer can be produced by a method known per se. Specifically, optical isomers can be obtained by using optically active synthetic intermediates or optically resolving racemates according to a conventional method. As the optical resolution method, a method known per se, for example, fractional recrystallization method, chiral column method, diastereomer method and the like are used.
  • Racemate and optically active compound for example, (+)-mandelic acid, ( ⁇ )-mandelic acid, (+)-tartaric acid, ( ⁇ )-tartaric acid, (+)-1-phenethylamine, (-)-1-phenethylamine, cinchonine, (-)-cinchonidine, brucine
  • Racemate and optically active compound for example, (+)-mandelic acid, ( ⁇ )-mandelic acid, (+)-tartaric acid, ( ⁇ )-tartaric acid, (+)-1-phenethylamine, (-)-1-phenethylamine, cinchonine, (-)-cinchonidine, brucine
  • optical isomers are added to a chiral column such as ENANTIO-OVM (manufactured by Tosoh Corporation) or CHIRAL series (manufactured by Daicel Corporation), and water, various buffers (eg, phosphate buffer)
  • the optical isomers are separated by developing an organic solvent (eg, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine, hexane, formic acid) as a single or mixed solution.
  • an organic solvent eg, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine, hexane, formic acid
  • the separation is performed using a chiral column such as CP-Chirasil-DeX CB (manufactured by GL Sciences).
  • a chiral column such as CP-Chirasil-DeX CB (manufactured by GL Sciences).
  • 3) Diastereomeric method A racemic mixture is converted into a diastereomeric mixture by chemical reaction with an optically active reagent, and this mixture is optically active through ordinary separation means (for example, fractional recrystallization, chromatography).
  • the compound (I) since the compound (I) has a secondary amino group and a carboxy group in the molecule, the compound and an optically active organic acid (for example, MTPA [ ⁇ -methoxy- ⁇ - (trifluoromethyl) phenylacetic acid], ( -)-Menthoxyacetic acid), optically active organic bases (eg phenylethylamine, 1- (1-naphthyl) ethylamine, cyclohexylethylamine, (+)-dehydroabiethylamine, tetrahydrofurfurylamine), or optically active alcohols ( For example, menthol, phenylethanol, 1,1′-binaphthol, 2-hexanol, mandelic acid ethyl ester) and the like can be subjected to a condensation reaction to obtain an ester or amide diastereomer. The separated diastereomer is converted into an optical isomer of Compound (I) by subjecting it
  • compound (I) contains stereoisomers, positional isomers, and rotational isomers, these are also included as compound (I), and each is obtained as a single product by a known synthesis method or separation method. be able to.
  • Compound (I) may be labeled with an isotope (eg, 3 H, 11 C, 14 C, 18 F, 35 S, 125 I) or the like. Furthermore, compound (I) may be any of hydrate, non-hydrate, solvate and solvate. Further, compound (I) may be a deuterium converter. Compound (I) may be crystalline or amorphous. When compound (I) is a crystal, it is included in compound (I) whether it is a single crystal form or a crystal form mixture. Crystals can be produced by crystallization by applying a crystallization method known per se.
  • the melting point is measured using, for example, a trace melting point measuring device (Yanako, MP-500D type or Buchi, B-545 type) or a DSC (differential scanning calorimetry) apparatus (SEIKO, EXSTAR6000). Mean melting point.
  • the melting point may vary depending on measurement equipment, measurement conditions, and the like.
  • the crystal in the present specification may be a crystal exhibiting a value different from the melting point described in the present specification as long as it is within a normal error range.
  • Compound (I) may be a pharmaceutically acceptable cocrystal or cocrystal salt.
  • co-crystals or co-crystal salts are two or more unique at room temperature, each having different physical properties (eg structure, melting point, heat of fusion, hygroscopicity, solubility and stability).
  • the cocrystal or cocrystal salt can be produced according to a cocrystallization method known per se.
  • the crystals of the present invention are excellent in physicochemical properties (eg, melting point, solubility, stability) and biological properties (eg, pharmacokinetics (absorbability, distribution, metabolism, excretion), expression of medicinal properties), and are extremely useful as pharmaceuticals. Useful.
  • a prodrug of compound (I) is a compound that is converted into compound (I), which is an active substance, by reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, enzymatically oxidized, reduced, hydrolyzed, etc.
  • a prodrug of compound (I) for example, (1) A compound wherein the amino group of compound (I) is acylated, alkylated or phosphorylated (eg, the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2 -Oxo-1,3-dioxolen-4-yl) methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated or tert-butylated compounds); (2) A compound in which the carboxy group of compound (I) is esterified or amidated (eg, the carboxy group of compound (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, Valoyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl
  • the prodrug of compound (I) is a compound that changes to compound (I) under physiological conditions as described in Hirokawa Shoten 1990, “Development of Drugs”, Volume 7, pages 163 to 198. It may be.
  • Compound (I) can be produced by a method known per se, Examples 1 to 18 or a method analogous thereto.
  • the raw material compound may be used as a salt, and as such a salt, those exemplified as the salt of the compound (I) are used.
  • a protective group generally used in peptide chemistry or the like is introduced into these groups.
  • the target compound can be obtained by removing the protecting group as necessary after the reaction.
  • Examples of the protecting group for amino group include formyl group, C 1-6 alkyl-carbonyl group, C 1-6 alkoxy-carbonyl group, benzoyl group, C 7-10 aralkyl-carbonyl group (eg, benzylcarbonyl), C 7-14 aralkyloxy-carbonyl group (eg, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl), trityl group, phthaloyl group, N, N-dimethylaminomethylene group, substituted silyl group (eg, trimethylsilyl, triethylsilyl, Dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), C 2-6 alkenyl groups (eg, 1-allyl) and the like. These groups may be substituted with 1 to 3 substituents selected from a halogen atom, a C 1-6 alkoxy group and a
  • Examples of the protecting group for the carboxyl group include a C 1-6 alkyl group, a C 7-11 aralkyl group (eg, benzyl), a phenyl group, a trityl group, a substituted silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), C 2-6 alkenyl groups (eg, 1-allyl) and the like. These groups may be substituted with 1 to 3 substituents selected from a halogen atom, a C 1-6 alkoxy group and a nitro group.
  • Examples of the protecting group for the hydroxy group include a C 1-6 alkyl group, a phenyl group, a trityl group, a C 7-10 aralkyl group (eg, benzyl), a formyl group, a C 1-6 alkyl-carbonyl group, a benzoyl group, C 7-10 aralkyl-carbonyl group (eg, benzylcarbonyl), 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, substituted silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert -Butyldiethylsilyl), C 2-6 alkenyl group (eg, 1-allyl) and the like. These groups may be substituted with 1 to 3 substituents selected from a halogen atom, a C 1-6 alkyl group, a C
  • Examples of the protecting group for the carbonyl group include cyclic acetals (eg, 1,3-dioxane), acyclic acetals (eg, di-C 1-6 alkylacetal) and the like.
  • Examples of the protecting group for the mercapto group include a C 1-6 alkyl group, a phenyl group, a trityl group, a C 7-10 aralkyl group (eg, benzyl), a C 1-6 alkyl-carbonyl group, a benzoyl group, a C 7- 10 aralkyl-carbonyl group (eg, benzylcarbonyl), C 1-6 alkoxy-carbonyl group, C 6-14 aryloxy-carbonyl group (eg, phenyloxycarbonyl), C 7-14 aralkyloxy-carbonyl group (eg, Benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl), 2-tetrahydropyranyl group, C 1-6 alkylamino-carbonyl group (eg, methylaminocarbonyl, ethylaminocarbonyl) and the like. These groups may be substituted with 1 to 3 substituents selected
  • the above-mentioned protecting group removal method can be carried out in accordance with a method known per se, for example, the method described in Protective Groups in Organic Synthesis, published by John Wiley and Sons (1980). . Specifically, acid, base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide (eg, trimethylsilyl iodide, trimethylsilyl bromide), etc. are used. And a reduction method.
  • a method known per se for example, the method described in Protective Groups in Organic Synthesis, published by John Wiley and Sons (1980). . Specifically, acid, base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialky
  • the compound obtained by each of the above production methods can be isolated and purified by known means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolution, chromatography and the like. Moreover, each raw material compound used in each of the above production methods can be isolated and purified by the same known means as described above. On the other hand, you may use these raw material compounds as a reaction mixture as it is as a raw material for the next step without isolation.
  • composition As a pharmaceutical composition, it is used as a preventive or therapeutic agent for various diseases described below for mammals (eg, humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, monkeys). be able to.
  • mammals eg, humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, monkeys.
  • a pharmacologically acceptable carrier various organic or inorganic carrier substances commonly used as pharmaceutical materials are used. Excipients, lubricants, binders, disintegrants in solid preparations; solvents in liquid preparations, dissolution aids It is formulated as an agent, suspending agent, isotonic agent, buffering agent, soothing agent and the like. If necessary, preparation additives such as preservatives, antioxidants, colorants, sweeteners and the like can also be used.
  • excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light
  • excipients include anhydrous silicic acid, synthetic aluminum silicate, and magnesium aluminate metasilicate.
  • lubricant examples include magnesium stearate, calcium stearate, talc and colloidal silica.
  • Preferred examples of the binder include pregelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxy Examples include propylmethylcellulose and polyvinylpyrrolidone.
  • disintegrant examples include lactose, sucrose, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, light anhydrous silicic acid, and low-substituted hydroxypropyl cellulose.
  • Suitable examples of the solvent include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, and cottonseed oil.
  • solubilizer examples include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate. Is mentioned.
  • suspending agent examples include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate; polyvinyl alcohol, polyvinylpyrrolidone , Hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose; polysorbates, and polyoxyethylene hydrogenated castor oil.
  • surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate
  • polyvinyl alcohol, polyvinylpyrrolidone Hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,
  • Preferable examples of the isotonic agent include sodium chloride, glycerin, D-mannitol, D-sorbitol and glucose.
  • buffer solutions of phosphate, acetate, carbonate, citrate and the like Preferable examples of the buffer include buffer solutions of phosphate, acetate, carbonate, citrate and the like.
  • a preferred example of the soothing agent is benzyl alcohol.
  • Preferable examples of the preservative include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid and sorbic acid.
  • Preferable examples of the antioxidant include sulfite and ascorbate.
  • the colorant examples include water-soluble edible tar dyes (eg, edible dyes such as edible red Nos. 2 and 3, edible yellows Nos. 4 and 5, edible blue Nos. 1 and 2, etc.), water-insoluble lake dyes (Eg, the aluminum salt of the water-soluble edible tar dye) and natural dyes (eg, ⁇ -carotene, chlorophyll, bengara).
  • water-soluble edible tar dyes eg, edible dyes such as edible red Nos. 2 and 3, edible yellows Nos. 4 and 5, edible blue Nos. 1 and 2, etc.
  • water-insoluble lake dyes Eg, the aluminum salt of the water-soluble edible tar dye
  • natural dyes eg, ⁇ -carotene, chlorophyll, bengara
  • Suitable examples of sweeteners include saccharin sodium, dipotassium glycyrrhizinate, aspartame, and stevia.
  • the medicament containing the compound of the present invention can be used alone or mixed with a pharmacologically acceptable carrier according to a method known per se as a method for producing a pharmaceutical preparation (eg, a method described in the Japanese Pharmacopoeia).
  • tablets including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.
  • pills powders, granules, capsules (including soft capsules and microcapsules), troches Agent, syrup, solution, emulsion, suspension, controlled release formulation (eg, immediate release formulation, sustained release formulation, sustained release microcapsule), aerosol, film agent (eg, orally disintegrating film, Oral mucosa adhesive film), injection (eg, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), drip, transdermal preparation, ointment, lotion, patch, sitting Suppositories (eg, rectal suppositories) Vaginal suppositories), pellets,
  • the pharmaceutical composition can be produced by a method commonly used in the field of pharmaceutical technology, for example, a method described in the Japanese Pharmacopoeia.
  • the content of the compound of the present invention in the pharmaceutical composition varies depending on the dosage form, the dose of the compound of the present invention, etc., but is, for example, about 0.1 to 100% by weight.
  • coating may be performed for the purpose of taste masking, enteric properties or sustainability.
  • coating base used for coating examples include sugar coating base, water-soluble film coating base, enteric film coating base and sustained-release film coating base.
  • sucrose is used, and one or more selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like may be used in combination.
  • water-soluble film coating base examples include cellulose polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, and methylhydroxyethylcellulose; polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E (trade name) ], Synthetic polymers such as polyvinylpyrrolidone; polysaccharides such as pullulan.
  • enteric film coating bases include cellulose polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate; methacrylic acid copolymer L [Eudragit L (trade name) ] Acrylic acid polymers such as methacrylic acid copolymer LD [Eudragit L-30D55 (trade name)], methacrylic acid copolymer S [Eudragit S (trade name)]; natural products such as shellac.
  • cellulose polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate
  • methacrylic acid copolymer L (Eudragit L (trade name) ]
  • Acrylic acid polymers such as methacrylic acid copolymer LD [Eudragit L-30D55 (trade name)], methacrylic acid copolymer
  • sustained-release film coating base examples include cellulose polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name)], ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit Acrylic polymer such as NE (trade name)].
  • cellulose polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name)], ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit Acrylic polymer such as NE (trade name)].
  • the above-mentioned coating bases may be used by mixing two or more of them in an appropriate ratio.
  • a light shielding agent such as titanium oxide or iron (III) oxide may be used.
  • the compound of the present invention has low toxicity (eg, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity), few side effects, and mammals (eg, humans, cows, horses, dogs, cats, Monkeys, mice, rats) can be used as preventive or therapeutic agents for various diseases or as diagnostic agents.
  • toxicity eg, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity
  • mammals eg, humans, cows, horses, dogs, cats, Monkeys, mice, rats
  • the compound of the present invention has an excellent glucagon antagonism.
  • the compound of the present invention blocks the action of glucagon by blocking the action of glucagon (for example, excessive sugar production from the liver, excessive secretion of growth hormone, excessive suppression of gastrointestinal motility, etc.) Can be improved. Therefore, the compound of the present invention can be useful as a glucagon antagonist, a sugar production inhibitor, a prophylactic or therapeutic agent for a disease involving enhanced glucagon action, and the like.
  • the compound of the present invention contains obesity, diabetes (eg, type 1 diabetes, type 2 diabetes, gestational diabetes, obesity type diabetes), hyperlipidemia (eg, hypertriglyceridemia, hypercholesterolemia, HypoHDLemia, postprandial hyperlipidemia), hypertension, heart failure, diabetic complications [eg, neuropathy, nephropathy, retinopathy, diabetic cardiomyopathy, cataract, macrovascular disorder, osteopenia, high diabetic Osmotic coma, infection (eg, respiratory infection, urinary tract infection, digestive tract infection, skin soft tissue infection, leg infection), diabetic gangrene, xerostomia, hearing loss, cerebrovascular disorder , Peripheral blood circulation disorders], metabolic syndrome (pathological conditions possessing three or more selected from hypertriglyceride (TG), low HDL cholesterol (HDL-C), hypertension, abdominal obesity and glucose intolerance), muscle loss Prevention or cure It can be used as agents.
  • the compound of the present invention is particularly useful as an agent for preventing or treating obesity and
  • diabetes is a fasting blood glucose level (glucose concentration in venous plasma) of 126 mg / dl or higher, and a 75 g oral glucose tolerance test (75 gOGTT) 2-hour value (glucose concentration in venous plasma) of 200 mg / dl or higher.
  • 75 gOGTT 75 g oral glucose tolerance test
  • a fasting blood glucose level (glucose concentration in venous plasma) is less than 110 mg / dl or a 75 g oral glucose tolerance test (75 g OGTT) 2 hour value (glucose concentration in venous plasma) is 140 mg / dl.
  • a state that is not “a state indicating less than dl” (normal type) is referred to as a “boundary type”.
  • diabetes is a fasting blood glucose level (glucose concentration in venous plasma) of 126 mg / dl or more, and a 75 g oral glucose tolerance test 2 hour value (glucose concentration in venous plasma) is 200 mg / dl. This is a state showing dl or more.
  • glucose intolerance is a fasting blood glucose level (glucose concentration in venous plasma) of less than 126 mg / dl, and a 75-g oral glucose tolerance test 2 hour value (glucose concentration in venous plasma). Is a state showing 140 mg / dl or more and less than 200 mg / dl. Furthermore, according to the report of ADA, the state where the fasting blood glucose level (glucose concentration in venous plasma) is 110 mg / dl or more and less than 126 mg / dl is called IFG (ImpairedpairFasting Glucose).
  • the IFG is a state where the 75 g oral glucose tolerance test 2 hour value (glucose concentration in venous plasma) is less than 140 mg / dl as IFG (Impaired Fasting Glycemia) Call.
  • the compound of the present invention is also used as a preventive or therapeutic agent for diabetes, borderline type, glucose intolerance, IFG (Impaired Fasting Glucose) and IFG (Impaired Fasting Glycemia) determined by the above-mentioned new criteria. Furthermore, the compound of the present invention can also prevent progression from borderline type, glucose intolerance, IFG (Impaired Fasting Glucose) or IFG (Impaired Fasting Glycemia) to diabetes.
  • the compound of the present invention is used for osteoporosis, cachexia (eg, cancer cachexia, tuberculosis cachexia, diabetic cachexia, blood disease cachexia, endocrine disease cachexia, infectious cachexia, heart disease) Cachexia or cachexia due to acquired immune deficiency syndrome), fatty liver, polycystic ovary syndrome, renal disease (eg, diabetic nephropathy, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis) , End stage renal disease), muscular dystrophy, myocardial infarction, angina, cerebrovascular disorder (eg, cerebral infarction, stroke), ischemia, coronary artery disease, non-Q wave infarction (non-Q-wave MI), congestive heart failure, ventricle Hypertrophy, new arrhythmia, intermittent claudication, peripheral obstructive arterial disease (eg, peripheral arterial disease), Alzheimer's disease, Parkinson's disease, anxiety
  • the compound of the present invention can also be used as a gastrointestinal motor function improving agent.
  • the compound of the present invention is also used for secondary prevention and suppression of progression of various diseases described above (eg, secondary prevention and suppression of progression of cardiovascular events such as myocardial infarction).
  • the administration target of the compound of the present invention is not particularly limited, but mammals (eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human etc.) are preferable.
  • the dose of the compound of the present invention varies depending on the administration subject, administration route, target disease, symptom, etc. For example, when orally administered to an adult diabetic patient, the dose is usually about 0.01 to 100 mg / kg body weight.
  • the dose is preferably 0.05 to 30 mg / kg body weight, more preferably 0.5 to 10 mg / kg body weight, and this amount is desirably administered once to three times a day.
  • the compound of the present invention is used in combination with a concomitant drug that does not adversely affect the compound of the present invention for the purpose of enhancing the action of the compound of the present invention, reducing the use amount of the compound of the present invention, preventing or treating complications, and improving the prognosis of life. be able to.
  • concomitant drugs include "diabetes therapeutics”, “diabetic complications”, “anti-obesity drugs”, “hypertension drugs”, “hyperlipidemic drugs”, “anti-atherosclerotic drugs” ”,“ Antithrombotic ”,“ diuretic ”and the like.
  • These concomitant drugs may be low molecular organic compounds, or may be macromolecules such as proteins, polypeptides, antibodies, and vaccines.
  • insulin preparations eg, animal insulin preparations extracted from bovine and porcine pancreas; human insulin preparations genetically engineered using Escherichia coli and yeast; insulin zinc; protamine insulin zinc
  • An insulin fragment or derivative eg, INS-1
  • an oral insulin preparation an insulin sensitizer (eg, pioglitazone or a salt thereof (preferably hydrochloride), rosiglitazone or a salt thereof (preferably maleic acid) Salt), Metaglidasen, AMG-131, Balaglitazone, MBX-2044, Riboglitazone, Aleglitazar, Chiglitazar, Lobeglitazone, PLX-204, PN -2034, GFT-505, THR-0921, WO2007 / 013694, WO2007 / 018314, WO2008 / 093639 WO2008 / 099794 compounds), ⁇ -glucosidase inhibitors (eg, vo
  • diabetic complication therapeutic agent examples include aldose reductase inhibitors (eg, tolrestat, epalrestat, zopolrestat, fidarestat, CT-112, ranirestat (AS-3201), ridressat), neurotrophic factor and its Increaser (eg, NGF, NT-3, BDNF, neurotrophin production / secretion promoter described in WO01 / 14372 (eg, 4- (4-chlorophenyl) -2- (2-methyl-1-imidazolyl)- 5- [3- (2-methylphenoxy) propyl] oxazole), compounds described in WO2004 / 039365), PKC inhibitors (eg, ruboxistaurin mesylate), AGE inhibitors (eg, ALT946, N) -Phenacyl thiazolium bromide (ALT766), EXO-226, pyridoline (Pyridorin), pyridoxamine), GABA
  • anti-obesity agents include monoamine uptake inhibitors (eg, phentermine, sibutramine, mazindol, floxetine, tesofensin), serotonin 2C receptor agonists (eg, lorcaserin), serotonin 6 receptor antagonists, histamine H3 receptor, GABA modulator (eg, topiramate), neuropeptide Y antagonist (eg, Berneperit), cannabinoid receptor antagonist (eg, rimonabant, taranaban), ghrelin antagonist, ghrelin receptor antagonist, ghrelin acyl Synthase inhibitors, opioid receptor antagonists (eg, GSK-1521498), orexin receptor antagonists, melanocortin 4 receptor agonists, 11 ⁇ -hydroxysteroid dehydrogenase inhibitors (eg, AZD-4017), pancreatic lipase inhibitors (Eg, orlistat, cetilistat), ⁇ 3 agonist ( E
  • angiotensin converting enzyme inhibitor eg, captopril, enalapril, delapril
  • angiotensin II antagonist eg, candesartan cilexetil, candesartan, losartan, losartan potassium, eprosartan, valsartan, telmisartan, Irbesartan, tasosartan, olmesartan, olmesartan medoxomil, azilsartan, azilsartan medoxomil
  • calcium antagonists eg, manidipine, nifedipine, amlodipine, efonidipine, nicardipine, sinyldipine
  • ⁇ -blockers eg, metoprolol, atenolol carprololol, prodrolol, ), Clonidine and the like.
  • hypolipidemic agent examples include HMG-CoA reductase inhibitors (eg, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin or salts thereof (eg, sodium salt, calcium salt) )), Squalene synthase inhibitors (eg, compounds described in WO97 / 10224, such as N-[[(3R, 5S) -1- (3-acetoxy-2,2-dimethylpropyl) -7-chloro-5 -(2,3-dimethoxyphenyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl] acetyl] piperidine-4-acetic acid), fibrate compounds ( Eg, bezafibrate, clofibrate, simfibrate, clinofibrate), anion exchange resin (eg, cholest
  • anti-arteriosclerotic agent examples include acylcoenzyme A cholesterol acyltransferase (ACAT) inhibitors (eg, K-604), LpPLA2 inhibitors (eg, dalapradiv, rilapradib), FLAP inhibitors (eg, AM103) AM803), 5LO inhibitors (eg, VIA-2291), sPLA2 inhibitors (eg, A-002), apoAI mimetic peptides (eg, D4F), HDL preparations (eg, CSL-111), and the like.
  • ACAT acylcoenzyme A cholesterol acyltransferase
  • LpPLA2 inhibitors eg, dalapradiv, rilapradib
  • FLAP inhibitors eg, AM103) AM803
  • 5LO inhibitors eg, VIA-2291
  • sPLA2 inhibitors eg, A-002
  • apoAI mimetic peptides eg, D4
  • antithrombotic agents examples include heparin (eg, heparin sodium, heparin calcium, enoxaparin sodium, dalteparin sodium), warfarin (eg, warfarin potassium), antithrombin drug (eg, , Argatroban (aragatroban), dabigatran, FXa inhibitors (eg, rivaroxaban, apixaban, edoxaban, YM150, WO02 / 06234, WO2004 / 048363, WO2005 / 030740, WO2005 / 058823 Or compounds described in WO2005 / 113504), thrombolytic drugs (eg, urokinase, tisokinase,reteplase, nateplase, monteplase, pamiteplase), platelet aggregation inhibitor (Eg, ticlopidine hydrochloride, clopidogrel, Excellent, E5555,
  • xanthine derivatives eg, sodium salicylate theobromine, calcium salicylate theobromine
  • thiazide preparations eg, etiazide, cyclopentiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benchylhydrochlorothiazide, Penfluthiazide, poly-5thiazide, meticlotiazide
  • anti-aldosterone preparation eg, spironolactone, triamterene
  • carbonic anhydrase inhibitor eg, acetazolamide
  • chlorobenzenesulfonamide preparation eg, chlorthalidone, mefluside, indapamide
  • examples thereof include azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, furosemide and the like.
  • the administration time of the aforementioned concomitant drug is not limited, and the compound of the present invention and the concomitant drug may be administered to the administration subject at the same time or may be administered with a time difference.
  • the dose of the concomitant drug may be determined according to the dose clinically used, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.
  • the administration form of the concomitant drug is not particularly limited, as long as the compound of the present invention and the concomitant drug are combined at the time of administration. Examples of such administration forms are 1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug, and 2) obtained by separately formulating the compound of the present invention and a concomitant drug.
  • Simultaneous administration of two preparations by the same administration route 3) Administration of two preparations obtained by separately formulating the compound of the present invention and a concomitant drug at different time intervals by the same administration route, 4) Simultaneous administration of two preparations obtained by separately formulating the compound of the invention and the concomitant drug by different administration routes, 5) Different two preparations obtained by separately formulating the compound of the present invention and the concomitant drug Administration with a time difference in the administration route (for example, administration in the order of the compound of the present invention and concomitant drugs, or administration in the reverse order) and the like.
  • the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, disease and the like.
  • the 1 H-NMR spectrum was measured with a Varian Gemini 300 (300 MHz) type and Bruker 300 (300 MHz) spectrometer using tetramethylsilane as an internal standard, and all ⁇ values were shown in ppm.
  • the numerical value shown in the mixed solvent is a volume mixing ratio of each solvent unless otherwise specified. % Means% by weight unless otherwise specified. Moreover, the ratio of the elution solvent in silica gel chromatography indicates a volume ratio unless otherwise specified. In this specification, room temperature (room temperature) represents a temperature of about 20 ° C. to about 30 ° C.
  • each symbol in an Example represents the following meaning.
  • DMSO dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • s singlet
  • d Doublet t: triplet
  • q quartet
  • dd double doublet
  • dt double triplet
  • quintet quintet
  • m multiplet
  • br s wide singlet
  • J Coupling constant
  • HPLC-MS was measured with the following apparatus and conditions.
  • Equipment Agilent G6100 series LC / MSD system (G6130A QMS SL series) ⁇ LC / MSD Single-Q SL G6130AA (Mass Detector) ⁇ ESI (Electro Spray Ionsource) G1948B ⁇ Multimode Ionsource G1978B ⁇ HTS PAL autosampler G1367C ⁇ Diode Array Detector G1315C
  • B MeCN (10 mM AcONH 4 )
  • Flow rate 1.2 ml / min Detection:
  • the reaction mixture was concentrated under reduced pressure, water (4 mL) was added, and the mixture was neutralized with 1N aqueous hydrochloric acid solution (2.18 mL). The resulting precipitate was collected by filtration to give the title object compound (399 mg, 92%) as a colorless amorphous solid.
  • a saturated aqueous sodium hydrogen carbonate solution cooled to 0 ° C. was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated, and the resulting residue was added to methyl 6-aminopyridine-3-carboxylate (2.33 g), sodium iodide (2.39 g), sodium carbonate (1.69 g), N , N-dimethylacetamide (20 mL) was added, and the mixture was stirred at 80 ° C. for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • Acetic acid (182 ⁇ L) was added to a mixture of the obtained oil, sodium cyanoborohydride (80 mg), and tetrahydrofuran (7 mL), and the mixture was stirred at room temperature for 20 min. Saturated aqueous sodium hydrogen carbonate solution was added to stop the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the title object compound (184 mg, 34%) as a white solid.
  • the fraction containing the optically active substance having the longer retention time is washed with a saturated aqueous sodium hydrogen carbonate solution, and the aqueous layer is extracted with ethyl acetate. The organic layers are combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate is concentrated to obtain an optically active form of the title target compound.
  • glucagon binding inhibitory action of the compound of the present invention was evaluated by the following method.
  • (1) Cloning of human glucagon receptor gene Cloning of the human glucagon receptor gene was performed by PCR reaction using human pancreatic Marathon-ready cDNA (Clontech) as a template and the following primer set.
  • GGR-U 5′-AATAGAATTCATGCCCCCCTGCCCAGCCACAG-3 ′ (SEQ ID NO: 1)
  • GGR-L 5′-CTAAGCGGCCCCTCAGAAGGGGCTCTCAGCCCAATCT-3 ′ (SEQ ID NO: 2)
  • Advantage 2 polymerase Advantage 2 polymerase
  • the obtained PCR product was subjected to agarose gel (1%) electrophoresis, and a DNA fragment of about 1.4 kb containing the glucagon receptor gene was recovered from the gel and then digested with restriction enzymes EcoRI and NotI. Restricted enzyme-treated DNA was electrophoresed on an agarose gel (1%), and a DNA fragment of about 1.4 kb was recovered and ligated to plasmid pMSR ⁇ neo digested with restriction enzymes EcoRI and NotI, and human glucagon receptor expression plasmid DNA “PMSR ⁇ neo / hGCGR” was prepared. The base sequence of the inserted fragment was confirmed and confirmed to be consistent with the target sequence.
  • the collected cells were washed with PBS, suspended in a homogenate buffer [10 mM NaHCO 3 (pH 7.4), 1 mM EDTA, complete EDTA-free (Roche, 1 tablet / 50 ml)], and a polytron cell disruption apparatus (Kinematica). Cells). The disrupted solution is centrifuged at 2,000 rpm for 10 minutes to recover the supernatant. The supernatant is centrifuged at 35,000 rpm for 60 minutes, and then the precipitate is buffered [20 mM Tris-HCl (pH 7.4), 5 mM. It was suspended in EDTA, complete EDTA-free (Roche, 1 tablet / 50 ml)] to obtain 452 mg of glucagon receptor membrane protein.
  • reaction solution is transferred from the reaction plate to a 96-well Unifilter GF / C plate (PerkinElmer) using a cell harvester (PerkinElmer), and the membrane fraction is drawn on the filter by aspiration. Was collected.
  • the filter was pre-soaked in 0.3% polyethyleneimine to prevent nonspecific adsorption of the labeled ligand.
  • the filter was washed 4 times with reaction buffer, dried at 42 ° C. for 2 hours, 25 ⁇ l of scintillator (MicroScint0; PerkinElmer) was added to each well, and a microplate scintillation counter (TopCount NXT TM ; PerkinElmer) The radioactivity was measured at
  • test compound (10 ⁇ M; 0.4%) was defined with the reaction rate of wells containing only 0.4% DMSO as 0% inhibition rate and the reaction rate of wells added with unlabeled glucagon (final concentration 1 ⁇ M) as 100% inhibition rate. Inhibition rate (%) of wells containing% DMSO solution was calculated. The results are shown in Table 1.
  • the compound of the present invention has an excellent glucagon binding inhibitory action.
  • Glucagon-induced blood glucose elevation inhibitory effect test (rat) Saturated SD rats (male, 7-9 weeks old) are fasted and 0.5% methylcellulose suspension containing compound (3-6 mg / kg body weight) (compound administration group, 10-13 mice per group) or 0.5% methylcellulose Suspensions (compound non-administered group, 12 mice per group) were orally administered, and 60 minutes later, glucagon (15 ⁇ g / kg body weight, Novo Nordisk Pharma Co., Ltd.) was administered subcutaneously. Blood was collected from the rat tail vein 20 minutes after administration of glucagon, and blood glucose was measured using a self-test glucose kit ACCU-CHEK (Roche Diagnostics Co., Ltd.).
  • the compound of the present invention has an excellent blood glucose elevation inhibitory action.
  • Formulation Example 1 (Manufacture of capsules) 1) 30 mg of the compound of Example 1 2) Fine powder cellulose 10 mg 3) Lactose 19 mg 4) Magnesium stearate 1 mg 60 mg total 1), 2), 3) and 4) are mixed and filled into gelatin capsules.
  • Formulation Example 2 Manufacture of tablets
  • the compound of the present invention has glucagon antagonism and is useful for the prevention or treatment of diabetes and the like.

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

Abstract

La présente invention concerne un agent prophylactique ou thérapeutique pour le diabète, qui possède une excellente efficacité pharmacologique. La présente invention concerne spécifiquement l'acide 3-{[(6-{[cyclohexyl(5-fluoro-1-méthyl-1H-indol-2-yl)méthyl]amino}pyridin-3-yl)carbonyl](méthyl)amino}-propanoïque, l'acide 3-{[(6-{[(5-chloro-1-méthyl-1H-indol-2-yl)(cyclohexyl)méthyl]amino}pyridin-3-yl)carbonyl](méthyl)-amino}propanoïque, l'acide 3-{[(6-{[(5-chloro-1-méthyl-1H-indol-2-yl)(cyclopentyl)méthyl]amino}pyridin-3-yl)-carbonyl](méthyl)amino}propanoïque, l'acide 3-{[(4-{[(5-chloro-3-méthylthiéno[2,3-c]-pyridin-2-yl)(cyclohexyl)méthyl]-amino}phényl)carbonyl](méthyl)amino}propanoïque, l'acide 3-{[(6-{[(6-chloro-3-méthylthiéno[3,2-c]pyridin-2-yl)(cyclohexyl)méthyl]amino}pyridin-3-yl)carbonyl](méthyl)-amino}propanoïque, l'acide 3-{[(4-{[(6-chloro-3-méthylthiéno[3,2-c]pyridin-2-yl)(cyclohexyl)-méthyl]amino}phényl)carbonyl](méthyl)amino}propanoïque, ou un sel de l'un quelconque des composés susmentionnés.
PCT/JP2010/065102 2009-09-04 2010-09-03 Composé hétérocyclique WO2011027849A1 (fr)

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US8507533B2 (en) 2011-02-08 2013-08-13 Pfizer Inc. Glucagon receptor modulators
WO2013147026A1 (fr) 2012-03-29 2013-10-03 武田薬品工業株式会社 Composé de type cycle aromatique
US8809342B2 (en) 2010-12-23 2014-08-19 Pfizer Inc. Glucagon receptor modulators
US8927577B2 (en) 2011-07-22 2015-01-06 Pfizer Inc. Quinolinyl glucagon receptor modulators

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US8809342B2 (en) 2010-12-23 2014-08-19 Pfizer Inc. Glucagon receptor modulators
US8933104B2 (en) 2010-12-23 2015-01-13 Pfizer Inc. Glucagon receptor modulators
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