WO2011027849A1 - Heterocyclic compound - Google Patents

Heterocyclic compound Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
amino
pyridin
chloro
compound
Prior art date
Application number
PCT/JP2010/065102
Other languages
French (fr)
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
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 武田薬品工業株式会社 filed Critical 武田薬品工業株式会社
Publication of WO2011027849A1 publication Critical patent/WO2011027849A1/en

Links

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.

Abstract

Disclosed is a prophylactic or therapeutic agent for diabetes, which has excellent pharmacological efficacy. Specifically disclosed is 3-{[(6-{[cyclohexyl(5-fluoro-1-methyl-1H-indol- 2-yl)methyl]amino}pyridin-3-yl)carbonyl](methyl)amino}- propanoic acid, 3-{[(6-{[(5-chloro-1-methyl-1H-indol-2- yl)(cyclohexyl)methyl]amino}pyridin-3-yl)carbonyl](methyl)- amino}propanoic acid, 3-{[(6-{[(5-chloro-1-methyl- 1H-indol-2-yl)(cyclopentyl)methyl]amino}pyridin-3-yl)- carbonyl](methyl)amino}propanoic acid, 3-{[(4-{[(5-chloro-3- methylthieno[2,3-c]-pyridin-2-yl)(cyclohexyl)methyl]- amino}phenyl)carbonyl](methyl)amino}propanoic acid, 3-{[(6- {[(6-chloro-3-methylthieno[3,2-c]pyridin-2- yl)(cyclohexyl)methyl]amino}pyridin-3-yl)carbonyl](methyl)- amino}propanoic acid, 3-{[(4-{[(6-chloro-3- methylthieno[3,2-c]pyridin-2-yl)(cyclohexyl)- methyl]amino}phenyl)carbonyl](methyl)amino}propanoic acid, or a salt of any one compound selected from the above-mentioned compounds.

Description

複素環化合物Heterocyclic compounds
　本発明は、糖尿病等の予防または治療に有用な、グルカゴン拮抗作用を有する複素環化合物に関する。 The present invention relates to a heterocyclic compound having glucagon antagonism useful for prevention or treatment of diabetes and the like.
　グルカゴンは、膵α細胞から分泌されるアミノ酸２９個からなる直鎖のペプチドホルモンであり、肝臓においてグリコーゲン分解と糖新生を促進する。糖尿病患者では、一般的に、グルカゴンの分泌および反応性が亢進しており、このことが高血糖の一因となっている。従って、グルカゴン受容体拮抗薬は、グルカゴンの作用を遮断することにより、肝臓からの過剰な糖産生を抑制することが可能であり、糖尿病治療薬として有用である。 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.
　グルカゴン拮抗剤としては、国際公開２００９／０５７７８４（特許文献１）および国際公開２００９／１１０５２０（特許文献２）記載の化合物などが知られている。 As glucagon antagonists, compounds described in International Publication 2009/057784 (Patent Document 1) and International Publication 2009/110520 (Patent Document 2) are known.
国際公開２００９／０５７７８４号パンフレットInternational publication 2009/057784 pamphlet 国際公開２００９／１１０５２０号パンフレットInternational Publication 2009/110520 Pamphlet
　糖尿病等の予防または治療に有用であり、かつ優れた薬効を有する化合物の開発が望まれている。 Development of compounds that are useful for the prevention or treatment of diabetes and the like and have excellent medicinal effects is desired.
　本発明者らは、以下の（１）～（６）に記載の化合物またはその塩（本明細書中、これら化合物をまとめて「化合物（Ｉ）」ということがある）が、グルカゴン拮抗作用を有し、糖尿病等の予防または治療剤として優れた薬効を有することを見出した。この知見に基づいて、本発明者らは、鋭意研究を行い、本発明を完成するに至った。即ち、本発明は、
（１）　3-{[(6-{[(5-クロロ-1-メチル-1H-インドール-2-イル)(シクロヘキシル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸またはその塩；
（２）　3-{[(6-{[シクロヘキシル(5-フルオロ-1-メチル-1H-インドール-2-イル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸またはその塩；
（３）　3-{[(6-{[(5-クロロ-1-メチル-1H-インドール-2-イル)(シクロペンチル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸またはその塩；
（４）　3-{[(4-{[(5-クロロ-3-メチルチエノ[2,3-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}フェニル)カルボニル](メチル)アミノ}プロパン酸またはその塩；
（５）　3-{[(6-{[(6-クロロ-3-メチルチエノ[3,2-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸またはその塩；
（６）　3-{[(4-{[(6-クロロ-3-メチルチエノ[3,2-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}フェニル)カルボニル](メチル)アミノ}プロパン酸またはその塩；
（７）　上記（１）～（６）のいずれか１項に記載の化合物またはその塩のプロドラッグ；
（８）　上記（１）～（６）のいずれか１項に記載の化合物またはその塩またはそのプロドラッグを含有してなる医薬；
（９）　グルカゴン拮抗剤である、上記（８）記載の医薬；
（１０）　糖産生抑制剤である、上記（８）記載の医薬；
（１１）　糖尿病の予防または治療剤である、上記（８）記載の医薬；
（１２）　上記（１）～（６）のいずれか１項に記載の化合物またはその塩またはそのプロドラッグを哺乳動物に投与することを特徴とする、該哺乳動物における糖尿病の予防または治療方法；
（１３）　糖尿病の予防または治療剤を製造するための、上記（１）～（６）のいずれか１項に記載の化合物またはその塩またはそのプロドラッグの使用；
等に関する。 The inventors of the present invention described in the following (1) to (6) or a salt thereof (in the present specification, these compounds may be collectively referred to as “compound (I)”) have 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. That is, 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] amino} phenyl) carbonyl] (methyl) amino} propane Acid or salt thereof;
(5) 3-{[(6-{[(6-Chloro-3-methylthieno [3,2-c] pyridin-2-yl) (cyclohexyl) methyl] amino} pyridin-3-yl) carbonyl] (methyl ) Amino} propanoic acid or salt thereof;
(6) 3-{[(4-{[(6-Chloro-3-methylthieno [3,2-c] pyridin-2-yl) (cyclohexyl) methyl] amino} phenyl) carbonyl] (methyl) amino} propane Acid or salt thereof;
(7) A prodrug of the compound or a salt thereof according to any one of (1) to (6) above;
(8) A medicament comprising the compound according to any one of (1) to (6) above, a salt thereof or a prodrug thereof;
(9) The medicament according to (8) above, which is a glucagon antagonist;
(10) The medicament according to (8) above, which is a sugar production inhibitor;
(11) The medicament according to (8) above, which is a preventive or therapeutic agent for diabetes;
(12) A method for the prophylaxis or treatment of diabetes in a mammal, comprising administering the compound according to any one of (1) to (6) above or a salt thereof or a prodrug thereof to the mammal;
(13) Use of the compound according to any one of (1) to (6) above or a salt thereof or a prodrug thereof for the manufacture of a prophylactic or therapeutic agent for diabetes;
Etc.
　本発明化合物は、グルカゴン拮抗作用を有し、かつ優れた薬効（血糖上昇抑制、血糖低下作用など）を有するので、糖尿病等の予防または治療に有用である。 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.
（発明の詳細な説明）
　化合物（Ｉ）における塩としては、薬理学的に許容される塩が好ましく、このような塩としては、例えば、無機塩基との塩、有機塩基との塩、無機酸との塩、有機酸との塩、塩基性または酸性アミノ酸との塩等が挙げられる。 (Detailed description of the invention)
The salt in compound (I) is preferably a pharmacologically acceptable salt. Examples of such a salt include a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, and an organic acid. And salts with basic or acidic amino acids.
　無機塩基との塩の好適な例としては、ナトリウム塩、カリウム塩等のアルカリ金属塩；カルシウム塩、マグネシウム塩等のアルカリ土類金属塩；アルミニウム塩；アンモニウム塩等が挙げられる。 Preferable examples of 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.
　有機塩基との塩の好適な例としては、トリメチルアミン、トリエチルアミン、ピリジン、ピコリン、エタノールアミン、ジエタノールアミン、トリエタノールアミン、トロメタミン［トリス（ヒドロキシメチル）メチルアミン］、ｔｅｒｔ－ブチルアミン、シクロヘキシルアミン、ベンジルアミン、ジシクロヘキシルアミン、Ｎ，Ｎ－ジベンジルエチレンジアミン等との塩が挙げられる。 Preferable examples of 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.
　無機酸との塩の好適な例としては、塩酸、臭化水素酸、硝酸、硫酸、リン酸等との塩が挙げられる。 Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
　有機酸との塩の好適な例としては、ギ酸、酢酸、トリフルオロ酢酸、フタル酸、フマル酸、シュウ酸、酒石酸、マレイン酸、クエン酸、コハク酸、リンゴ酸、メタンスルホン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸等との塩が挙げられる。 Preferable examples of 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.
　塩基性アミノ酸との塩の好適な例としては、アルギニン、リジン、オルニチン等との塩が挙げられる。 Preferable examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like.
　酸性アミノ酸との塩の好適な例としては、アスパラギン酸、グルタミン酸等との塩が挙げられる。 Preferable examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like.
　化合物（Ｉ）は、自体公知の方法またはそれに準ずる方法、例えば、後述の実施例に記載の方法に従って製造することができる。化合物（Ｉ）が遊離化合物として得られた場合には、自体公知の方法またはそれに準ずる方法により、目的とする塩に変換することができ、逆に、塩で得られた場合には、自体公知の方法またはそれに準ずる方法により、遊離体または目的とする他の塩に変換することができる。 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. 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.
　化合物（Ｉ）は、ラセミ体、Ｒ体及びＳ体などの光学活性体を含む。このような化合物（Ｉ）の光学異性体の具体例を以下に示す：
（１）　3-{[(6-{[(5-クロロ-1-メチル-1H-インドール-2-イル)(シクロヘキシル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸の光学異性体としては、
3-{[(6-{[(R)-(5-クロロ-1-メチル-1H-インドール-2-イル)(シクロヘキシル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸、および
3-{[(6-{[(S)-(5-クロロ-1-メチル-1H-インドール-2-イル)(シクロヘキシル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸
が挙げられる；
（２）　3-{[(6-{[シクロヘキシル(5-フルオロ-1-メチル-1H-インドール-2-イル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸の光学異性体としては、
3-{[(6-{[(R)-シクロヘキシル(5-フルオロ-1-メチル-1H-インドール-2-イル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸、および
3-{[(6-{[(S)-シクロヘキシル(5-フルオロ-1-メチル-1H-インドール-2-イル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸
が挙げられる；
（３）　3-{[(6-{[(5-クロロ-1-メチル-1H-インドール-2-イル)(シクロペンチル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸の光学異性体としては、
3-{[(6-{[(R)-(5-クロロ-1-メチル-1H-インドール-2-イル)(シクロペンチル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸、および
3-{[(6-{[(S)-(5-クロロ-1-メチル-1H-インドール-2-イル)(シクロペンチル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸
が挙げられる；
（４）　3-{[(4-{[(5-クロロ-3-メチルチエノ[2,3-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}フェニル)カルボニル](メチル)アミノ}プロパン酸の光学異性体としては、
3-{[(4-{[(R)-(5-クロロ-3-メチルチエノ[2,3-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}フェニル)カルボニル](メチル)アミノ}プロパン酸、および
3-{[(4-{[(S)-(5-クロロ-3-メチルチエノ[2,3-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}フェニル)カルボニル](メチル)アミノ}プロパン酸
が挙げられる；
（５）　3-{[(6-{[(6-クロロ-3-メチルチエノ[3,2-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸の光学異性体としては、
3-{[(6-{[(R)-(6-クロロ-3-メチルチエノ[3,2-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸、および
3-{[(6-{[(S)-(6-クロロ-3-メチルチエノ[3,2-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸
が挙げられる；
（６）　3-{[(4-{[(6-クロロ-3-メチルチエノ[3,2-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}フェニル)カルボニル](メチル)アミノ}プロパン酸の光学異性体としては、
3-{[(4-{[(R)-(6-クロロ-3-メチルチエノ[3,2-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}フェニル)カルボニル](メチル)アミノ}プロパン酸、および
3-{[(4-{[(S)-(6-クロロ-3-メチルチエノ[3,2-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}フェニル)カルボニル](メチル)アミノ}プロパン酸
が挙げられる。 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;
(2) 3-{[(6-{[cyclohexyl (5-fluoro-1-methyl-1H-indol-2-yl) methyl] amino} pyridin-3-yl) carbonyl] (methyl) amino} propanoic acid As optical isomers,
3-{[(6-{[(R) -Cyclohexyl (5-fluoro-1-methyl-1H-indol-2-yl) methyl] amino} pyridin-3-yl) carbonyl] (methyl) amino} propanoic acid ,and
3-{[(6-{[(S) -cyclohexyl (5-fluoro-1-methyl-1H-indol-2-yl) methyl] amino} pyridin-3-yl) carbonyl] (methyl) amino} propanoic acid Can be mentioned;
(3) 3-{[(6-{[(5-Chloro-1-methyl-1H-indol-2-yl) (cyclopentyl) 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) (cyclopentyl) methyl] amino} pyridin-3-yl) carbonyl] (methyl) amino} Propanoic acid, and
3-{[(6-{[(S)-(5-Chloro-1-methyl-1H-indol-2-yl) (cyclopentyl) methyl] amino} pyridin-3-yl) carbonyl] (methyl) amino} And propanoic acid;
(4) 3-{[(4-{[(5-Chloro-3-methylthieno [2,3-c] pyridin-2-yl) (cyclohexyl) methyl] amino} phenyl) carbonyl] (methyl) amino} propane As an optical isomer of acid,
3-{[(4-{[(R)-(5-Chloro-3-methylthieno [2,3-c] pyridin-2-yl) (cyclohexyl) methyl] amino} phenyl) carbonyl] (methyl) amino} Propanoic acid, and
3-{[(4-{[(S)-(5-Chloro-3-methylthieno [2,3-c] pyridin-2-yl) (cyclohexyl) methyl] amino} phenyl) carbonyl] (methyl) amino} And propanoic acid;
(5) 3-{[(6-{[(6-Chloro-3-methylthieno [3,2-c] pyridin-2-yl) (cyclohexyl) methyl] amino} pyridin-3-yl) carbonyl] (methyl ) Amino} propanoic acid optical isomers include:
3-{[(6-{[(R)-(6-Chloro-3-methylthieno [3,2-c] pyridin-2-yl) (cyclohexyl) methyl] amino} pyridin-3-yl) carbonyl] ( Methyl) amino} propanoic acid, and
3-{[(6-{[(S)-(6-Chloro-3-methylthieno [3,2-c] pyridin-2-yl) (cyclohexyl) methyl] amino} pyridin-3-yl) carbonyl] ( Methyl) amino} propanoic acid;
(6) 3-{[(4-{[(6-Chloro-3-methylthieno [3,2-c] pyridin-2-yl) (cyclohexyl) methyl] amino} phenyl) carbonyl] (methyl) amino} propane As an optical isomer of acid,
3-{[(4-{[(R)-(6-Chloro-3-methylthieno [3,2-c] pyridin-2-yl) (cyclohexyl) methyl] amino} phenyl) carbonyl] (methyl) amino} Propanoic acid, and
3-{[(4-{[(S)-(6-Chloro-3-methylthieno [3,2-c] pyridin-2-yl) (cyclohexyl) methyl] amino} phenyl) carbonyl] (methyl) amino} Propanoic acid is mentioned.
　光学異性体は、自体公知の方法により製造することができる。具体的には、光学活性な合成中間体を用いるか、またはラセミ体を、常法に従って、光学分割することにより、光学異性体を得ることができる。
　光学分割法としては、自体公知の方法、例えば、分別再結晶法、キラルカラム法、ジアステレオマー法等が用いられる。
　１）分別再結晶法
　ラセミ体と光学活性な化合物（例えば、（＋）－マンデル酸、（－）－マンデル酸、（＋）－酒石酸、（－）－酒石酸、（＋）－１－フェネチルアミン、（－）－１－フェネチルアミン、シンコニン、（－）－シンコニジン、ブルシン）との塩を形成させ、これを分別再結晶法によって分離し、所望により、中和工程を経てフリーの光学異性体を得る方法。
　２）キラルカラム法
　ラセミ体またはその塩を光学異性体分離用カラム（キラルカラム）を用いて分離する方法。例えば、液体クロマトグラフィーの場合、ＥＮＡＮＴＩＯ－ＯＶＭ（トーソー社製）あるいは、ダイセル社製　ＣＨＩＲＡＬシリーズなどのキラルカラムに光学異性体の混合物を添加し、水、種々の緩衝液（例、リン酸緩衝液）、有機溶媒（例、エタノール、メタノール、イソプロパノール、アセトニトリル、トリフルオロ酢酸、ジエチルアミン、ヘキサン、ギ酸）を単独あるいは混合した溶液として展開させることにより、光学異性体を分離する。また、例えば、ガスクロマトグラフィーの場合、ＣＰ－Ｃｈｉｒａｓｉｌ－ＤｅＸ　ＣＢ（ジーエルサイエンス社製）などのキラルカラムを使用して分離する。
　３）ジアステレオマー法
　ラセミ体の混合物を光学活性な試薬との化学反応によってジアステレオマーの混合物とし、これを通常の分離手段（例えば、分別再結晶、クロマトグラフィー法）などを経て光学活性な単一物質とした後、加水分解反応などの化学的な処理により光学活性な試薬部位を切り離すことにより光学異性体を得る方法。例えば、化合物（Ｉ）は分子内に２級アミノ基およびカルボキシ基を有するので、該化合物と光学活性な有機酸（例えば、ＭＴＰＡ〔α－メトキシ－α－（トリフルオロメチル）フェニル酢酸〕、（－）－メントキシ酢酸）、光学活性な有機塩基（例えば、フェニルエチルアミン、1-(1-ナフチル)エチルアミン、シクロヘキシルエチルアミン、(+)-デヒドロアビエチルアミン、テトラヒドロフルフリルアミン）、または光学活性なアルコール体（例えば、メントール、 フェニルエタノール、1,1'-ビナフトール、2-ヘキサノール、マンデル酸エチルエステル）などとを縮合反応に付すことにより、エステル体またはアミド体のジアステレオマーが得られる。分離されたジアステレオマーは、酸加水分解あるいは塩基性加水分解反応などに付すことにより、化合物（Ｉ）の光学異性体に変換される。 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.
1) Fractional recrystallization method Racemate and optically active compound (for example, (+)-mandelic acid, (−)-mandelic acid, (+)-tartaric acid, (−)-tartaric acid, (+)-1-phenethylamine, (-)-1-phenethylamine, cinchonine, (-)-cinchonidine, brucine), and this is separated by fractional recrystallization. If desired, a free optical isomer is obtained through a neutralization step. Method.
2) Chiral column method A method in which a racemate or a salt thereof is separated using a column for separation of optical isomers (chiral column). For example, in the case of liquid chromatography, a mixture of optical isomers is 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. Further, for example, in the case of gas chromatography, the separation is performed using 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). A method of obtaining optical isomers by separating optically active reagent sites by chemical treatment such as hydrolysis after making a single substance. For example, 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 [α-methoxy-α- (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 to an acid hydrolysis or a basic hydrolysis reaction.
　化合物（Ｉ）が、立体異性体、位置異性体、回転異性体を含有する場合には、これらも化合物（Ｉ）として含有されるとともに、自体公知の合成手法、分離手法によりそれぞれを単品として得ることができる。 When 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.
　化合物（Ｉ）は、同位元素（例、３Ｈ、１１Ｃ、１４Ｃ、１８F、３５Ｓ、１２５Ｉ）等で標識されていてもよい。
　さらに、化合物（Ｉ）は、水和物、非水和物、溶媒和物、無溶媒和物のいずれでもよい。
　さらに、化合物（Ｉ）は、重水素変換体であってもよい。
　化合物（Ｉ）は、結晶であっても無晶形であってもよい。化合物（Ｉ）が結晶である場合、結晶形が単一であっても結晶形混合物であっても化合物（Ｉ）に包含される。結晶は、自体公知の結晶化法を適用して、結晶化することによって製造することができる。
　本明細書中、融点は、例えば、微量融点測定器（ヤナコ、ＭＰ－５００Ｄ型またはＢｕｃｈｉ、Ｂ－５４５型）またはＤＳＣ（示差走査熱量分析）装置（ＳＥＩＫＯ、ＥＸＳＴＡＲ６０００）等を用いて測定される融点を意味する。
　一般に、融点は、測定機器、測定条件等によって変動する場合がある。本明細書中の結晶は、通常の誤差範囲内であれば、本明細書に記載の融点と異なる値を示す結晶であってもよい。
　化合物（Ｉ）は、薬学的に許容され得る共結晶または共結晶塩であってもよい。ここで、共結晶または共結晶塩とは、各々が異なる物理的特性（例えば、構造、融点、融解熱、吸湿性、溶解性および安定性等）を持つ、室温で二種またはそれ以上の独特な固体から構成される結晶性物質を意味する。共結晶または共結晶塩は、自体公知の共結晶化法に従い製造することができる。本発明の結晶は、物理化学的性質（例、融点、溶解度、安定性）および生物学的性質（例、体内動態（吸収性、分布、代謝、***）、薬効発現）に優れ、医薬として極めて有用である。 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.
In the present specification, 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.
In general, 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. Here, 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). Means a crystalline substance composed of a solid. 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.
　化合物（Ｉ）のプロドラッグは、生体内における生理条件下で酵素や胃酸等による反応により、活性本体である化合物（Ｉ）に変換する化合物、すなわち酵素的に酸化、還元、加水分解等を起こして化合物（Ｉ）に変化する化合物、胃酸等により加水分解等を起こして化合物（Ｉ）に変化する化合物である。 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 compound that changes to compound (I), or a compound that undergoes hydrolysis or the like by gastric acid or the like and changes to compound (I).
　化合物（Ｉ）のプロドラッグとしては、例えば、
（１）化合物（Ｉ）のアミノ基がアシル化、アルキル化またはリン酸化された化合物（例、化合物（Ｉ）のアミノ基がエイコサノイル化、アラニル化、ペンチルアミノカルボニル化、（５－メチル－２－オキソ－１，３－ジオキソレン－４－イル）メトキシカルボニル化、テトラヒドロフラニル化、ピロリジルメチル化、ピバロイルオキシメチル化またはｔｅｒｔ－ブチル化された化合物）；
（２）化合物（Ｉ）のカルボキシ基がエステル化またはアミド化された化合物（例、化合物（Ｉ）のカルボキシ基がエチルエステル化、フェニルエステル化、カルボキシメチルエステル化、ジメチルアミノメチルエステル化、ピバロイルオキシメチルエステル化、エトキシカルボニルオキシエチルエステル化、フタリジルエステル化、（５－メチル－２－オキソ－１，３－ジオキソレン－４－イル）メチルエステル化、シクロヘキシルオキシカルボニルエチルエステル化またはメチルアミド化された化合物）等が挙げられる。
　これらの化合物は、自体公知の方法によって化合物（Ｉ）から製造することができる。 As 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 esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification or methylamide Compound) and the like.
These compounds can be produced from compound (I) by a method known per se.
　また、化合物（Ｉ）のプロドラッグは、広川書店１９９０年刊「医薬品の開発」第７巻分子設計１６３頁から１９８頁に記載されているような、生理的条件において化合物（Ｉ）に変化するものであってもよい。 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.
　以下、化合物（Ｉ）の製造法について説明する。
　化合物（Ｉ）は、自体公知の方法、実施例１ないし１８またはこれらに準ずる方法により製造することができる。なお、以下の各製造法において、原料化合物は塩として用いてもよく、このような塩としては、前記化合物（Ｉ）の塩として例示したものが用いられる。 Hereafter, the manufacturing method of compound (I) is demonstrated.
Compound (I) can be produced by a method known per se, Examples 1 to 18 or a method analogous thereto. In each of the following production methods, 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.
　前記の各反応において、原料化合物が置換基としてアミノ基、カルボキシル基、ヒドロキシ基、カルボニル基またはメルカプト基を有する場合、これらの基にペプチド化学等で一般的に用いられるような保護基が導入されていてもよく、反応後に必要に応じて保護基を除去することにより目的化合物を得ることができる。 In each of the above reactions, when the raw material compound has an amino group, carboxyl group, hydroxy group, carbonyl group or mercapto group as a substituent, 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.
　アミノ基の保護基としては、例えば、ホルミル基、Ｃ１－６アルキル－カルボニル基、Ｃ１－６アルコキシ－カルボニル基、ベンゾイル基、Ｃ７－１０アラルキル－カルボニル基（例、ベンジルカルボニル）、Ｃ７－１４アラルキルオキシ－カルボニル基（例、ベンジルオキシカルボニル、９－フルオレニルメトキシカルボニル）、トリチル基、フタロイル基、Ｎ，Ｎ－ジメチルアミノメチレン基、置換シリル基（例、トリメチルシリル、トリエチルシリル、ジメチルフェニルシリル、ｔｅｒｔ－ブチルジメチルシリル、ｔｅｒｔ－ブチルジエチルシリル）、Ｃ２－６アルケニル基（例、１－アリル）等が挙げられる。これらの基は、ハロゲン原子、Ｃ１－６アルコキシ基およびニトロ基から選ばれる１ないし３個の置換基で置換されていてもよい。 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 nitro group.
　カルボキシル基の保護基としては、例えば、Ｃ１－６アルキル基、Ｃ７－１１アラルキル基（例、ベンジル）、フェニル基、トリチル基、置換シリル基（例、トリメチルシリル、トリエチルシリル、ジメチルフェニルシリル、ｔｅｒｔ－ブチルジメチルシリル、ｔｅｒｔ－ブチルジエチルシリル）、Ｃ２－６アルケニル基（例、１－アリル）等が挙げられる。これらの基は、ハロゲン原子、Ｃ１－６アルコキシ基およびニトロ基から選ばれる１ないし３個の置換基で置換されていてもよい。 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.
　ヒドロキシ基の保護基としては、例えば、Ｃ１－６アルキル基、フェニル基、トリチル基、Ｃ７－１０アラルキル基（例、ベンジル）、ホルミル基、Ｃ１－６アルキル－カルボニル基、ベンゾイル基、Ｃ７－１０アラルキル－カルボニル基（例、ベンジルカルボニル）、２－テトラヒドロピラニル基、２－テトラヒドロフラニル基、置換シリル基（例、トリメチルシリル、トリエチルシリル、ジメチルフェニルシリル、ｔｅｒｔ－ブチルジメチルシリル、ｔｅｒｔ－ブチルジエチルシリル）、Ｃ２－６アルケニル基（例、１－アリル）等が挙げられる。これらの基は、ハロゲン原子、Ｃ１－６アルキル基、Ｃ１－６アルコキシ基およびニトロ基から選ばれる１ないし３個の置換基で置換されていてもよい。 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 1-6 alkoxy group and a nitro group.
　カルボニル基の保護基としては、例えば、環状アセタール（例、１，３－ジオキサン）、非環状アセタール（例、ジ－Ｃ１－６アルキルアセタール）等が挙げられる。 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.
　メルカプト基の保護基としては、例えば、Ｃ１－６アルキル基、フェニル基、トリチル基、Ｃ７－１０アラルキル基（例、ベンジル）、Ｃ１－６アルキル－カルボニル基、ベンゾイル基、Ｃ７－１０アラルキル－カルボニル基（例、ベンジルカルボニル）、Ｃ１－６アルコキシ－カルボニル基、Ｃ６－１４アリールオキシ－カルボニル基（例、フェニルオキシカルボニル）、Ｃ７－１４アラルキルオキシ－カルボニル基（例、ベンジルオキシカルボニル、９－フルオレニルメトキシカルボニル）、２－テトラヒドロピラニル基、Ｃ１－６アルキルアミノ－カルボニル基（例、メチルアミノカルボニル、エチルアミノカルボニル）等が挙げられる。これらの基は、ハロゲン原子、Ｃ１－６アルキル基、Ｃ１－６アルコキシ基およびニトロ基から選ばれる１ないし３個の置換基で置換されていてもよい。 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 from a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group and a nitro group.
　上記した保護基の除去方法は、自体公知の方法、例えば、プロテクティブ　グループス　イン　オーガニック　シンセシス（Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ）、Ｊｏｈｎ　Ｗｉｌｅｙ　ａｎｄ　Ｓｏｎｓ刊（１９８０）に記載の方法等に準じて行うことができる。具体的には、酸、塩基、紫外光、ヒドラジン、フェニルヒドラジン、Ｎ－メチルジチオカルバミン酸ナトリウム、テトラブチルアンモニウムフルオリド、酢酸パラジウム、トリアルキルシリルハライド(例、トリメチルシリルヨージド、トリメチルシリルブロミド)等を使用する方法、還元法等が挙げられる。 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.
　上記の各製造法により得られる化合物は、濃縮、減圧濃縮、溶媒抽出、晶出、再結晶、転溶、クロマトグラフィー等の公知の手段により単離精製することができる。また、上記の各製造法において用いられる各原料化合物は、前記と同様の公知の手段によって単離精製することができる。一方、これら原料化合物を単離することなく、そのまま反応混合物として、次の工程の原料として用いてもよい。 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.
　化合物（Ｉ）およびそのプロドラッグ（本明細書中、これらをまとめて「本発明化合物」と略記することがある）は、毒性が低く、そのまま、または薬理学的に許容し得る担体等と混合して医薬組成物とすることにより、哺乳動物（例、ヒト、マウス、ラット、ウサギ、イヌ、ネコ、ウシ、ウマ、ブタ、サル）に対して、後述する各種疾患の予防または治療剤として用いることができる。 Compound (I) and prodrugs thereof (in the present specification, these may be abbreviated as “the compound of the present invention” together) have low toxicity and are mixed as such or with a pharmacologically acceptable carrier. By using the 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.
　薬理学的に許容し得る担体としては、製剤素材として慣用の各種有機または無機担体物質が用いられ、固形製剤における賦形剤、滑沢剤、結合剤、崩壊剤；液状製剤における溶剤、溶解補助剤、懸濁化剤、等張化剤、緩衝剤、無痛化剤等として配合される。また必要に応じて、防腐剤、抗酸化剤、着色剤、甘味剤等の製剤添加物を用いることもできる。 As 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.
　賦形剤の好適な例としては、乳糖、白糖、Ｄ－マンニトール、Ｄ－ソルビトール、デンプン、α化デンプン、デキストリン、結晶セルロース、低置換度ヒドロキシプロピルセルロース、カルボキシメチルセルロースナトリウム、アラビアゴム、プルラン、軽質無水ケイ酸、合成ケイ酸アルミニウム、メタケイ酸アルミン酸マグネシウムが挙げられる。 Preferable examples of excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light Examples thereof include anhydrous silicic acid, synthetic aluminum silicate, and magnesium aluminate metasilicate.
　滑沢剤の好適な例としては、ステアリン酸マグネシウム、ステアリン酸カルシウム、タルク、コロイドシリカが挙げられる。 Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc and colloidal silica.
　結合剤の好適な例としては、α化デンプン、ショ糖、ゼラチン、アラビアゴム、メチルセルロース、カルボキシメチルセルロース、カルボキシメチルセルロースナトリウム、結晶セルロース、白糖、Ｄ－マンニトール、トレハロース、デキストリン、プルラン、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドンが挙げられる。 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.
　崩壊剤の好適な例としては、乳糖、白糖、デンプン、カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム、クロスカルメロースナトリウム、カルボキシメチルスターチナトリウム、軽質無水ケイ酸、低置換度ヒドロキシプロピルセルロースが挙げられる。 Preferable examples of the disintegrant include lactose, sucrose, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, light anhydrous silicic acid, and low-substituted hydroxypropyl cellulose.
　溶剤の好適な例としては、注射用水、生理的食塩水、リンゲル液、アルコール、プロピレングリコール、ポリエチレングリコール、ゴマ油、トウモロコシ油、オリーブ油、綿実油が挙げられる。 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.
　溶解補助剤の好適な例としては、ポリエチレングリコール、プロピレングリコール、Ｄ－マンニトール、トレハロース、安息香酸ベンジル、エタノール、トリスアミノメタン、コレステロール、トリエタノールアミン、炭酸ナトリウム、クエン酸ナトリウム、サリチル酸ナトリウム、酢酸ナトリウムが挙げられる。 Preferable examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate. Is mentioned.
　懸濁化剤の好適な例としては、ステアリルトリエタノールアミン、ラウリル硫酸ナトリウム、ラウリルアミノプロピオン酸、レシチン、塩化ベンザルコニウム、塩化ベンゼトニウム、モノステアリン酸グリセリン等の界面活性剤；ポリビニルアルコール、ポリビニルピロリドン、カルボキシメチルセルロースナトリウム、メチルセルロース、ヒドロキシメチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース等の親水性高分子；ポリソルベート類、ポリオキシエチレン硬化ヒマシ油が挙げられる。 Suitable examples of the suspending agent 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.
　等張化剤の好適な例としては、塩化ナトリウム、グリセリン、Ｄ－マンニトール、Ｄ－ソルビトール、ブドウ糖が挙げられる。 Preferable examples of the isotonic agent include sodium chloride, glycerin, D-mannitol, D-sorbitol and glucose.
　緩衝剤の好適な例としては、リン酸塩、酢酸塩、炭酸塩、クエン酸塩等の緩衝液が挙げられる。
　無痛化剤の好適な例としては、ベンジルアルコールが挙げられる。 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.
　防腐剤の好適な例としては、パラオキシ安息香酸エステル類、クロロブタノール、ベンジルアルコール、フェネチルアルコール、デヒドロ酢酸、ソルビン酸が挙げられる。
　抗酸化剤の好適な例としては、亜硫酸塩、アスコルビン酸塩等が挙げられる。 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.
　着色剤の好適な例としては、水溶性食用タール色素（例、食用赤色２号および３号、食用黄色４号および５号、食用青色１号および２号等の食用色素）、水不溶性レーキ色素（例、前記水溶性食用タール色素のアルミニウム塩）、天然色素（例、β－カロチン、クロロフィル、ベンガラ）が挙げられる。 Preferred examples of the colorant 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, β-carotene, chlorophyll, bengara).
　甘味剤の好適な例としては、サッカリンナトリウム、グリチルリチン酸二カリウム、アスパルテーム、ステビアが挙げられる。 Suitable examples of sweeteners include saccharin sodium, dipotassium glycyrrhizinate, aspartame, and stevia.
　本発明化合物を含有する医薬は、医薬製剤の製造法として自体公知の方法（例、日本薬局方記載の方法等）に従って、本発明化合物を単独で、または薬理学的に許容される担体と混合して、例えば錠剤（糖衣錠、フィルムコーティング錠、舌下錠、口腔内崩壊錠、バッカル錠等を含む）、丸剤、散剤、顆粒剤、カプセル剤（ソフトカプセル剤、マイクロカプセル剤を含む）、トローチ剤、シロップ剤、液剤、乳剤、懸濁剤、放出制御製剤（例、速放性製剤、徐放性製剤、徐放性マイクロカプセル剤）、エアゾール剤、フィルム剤（例、口腔内崩壊フィルム、口腔粘膜貼付フィルム）、注射剤（例、皮下注射剤、静脈内注射剤、筋肉内注射剤、腹腔内注射剤）、点滴剤、経皮吸収型製剤、軟膏剤、ローション剤、貼付剤、坐剤（例、肛門坐剤、膣坐剤）、ペレット、経鼻剤、経肺剤（吸入剤）、点眼剤等として、経口的または非経口的（例、静脈内、筋肉内、皮下、臓器内、鼻腔内、皮内、点眼、脳内、直腸内、膣内、腹腔内、腫瘍内部、腫瘍の近位等への投与および直接的な病巣への投与）に安全に投与することができる。 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). For example, 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, nasal preparations, pulmonary preparations (inhalants), eye drops, etc., orally or parenterally (eg, intravenous, intramuscular, subcutaneous, intraorgan, intranasal, intradermal, Ophthalmic, intracerebral, intrarectal, intravaginal, intraperitoneal, intratumoral, proximal to the tumor, etc. and direct administration to the lesion).
　医薬組成物は、製剤技術分野において慣用の方法、例えば、日本薬局方に記載の方法等により製造することができる。 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.
　なお、医薬組成物中の本発明化合物の含量は、剤形、本発明化合物の投与量等により異なるが、例えば、約０．１～１００重量％である。 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.
　経口剤を製造する際には、必要により、味のマスキング、腸溶性または持続性を目的として、コーティングを行ってもよい。 When manufacturing an oral preparation, if necessary, coating may be performed for the purpose of taste masking, enteric properties or sustainability.
　コーティングに用いられるコーティング基剤としては、例えば、糖衣基剤、水溶性フィルムコーティング基剤、腸溶性フィルムコーティング基剤、徐放性フィルムコーティング基剤が挙げられる。 Examples of the coating base used for coating include sugar coating base, water-soluble film coating base, enteric film coating base and sustained-release film coating base.
　糖衣基剤としては、白糖が用いられ、さらに、タルク、沈降炭酸カルシウム、ゼラチン、アラビアゴム、プルラン、カルナバロウ等から選ばれる１種または２種以上を併用してもよい。 As the sugar 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.
　水溶性フィルムコーティング基剤としては、例えば、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ヒドロキシエチルセルロース、メチルヒドロキシエチルセルロース等のセルロース系高分子；ポリビニルアセタールジエチルアミノアセテート、アミノアルキルメタアクリレートコポリマーＥ〔オイドラギットＥ（商品名）〕、ポリビニルピロリドン等の合成高分子；プルラン等の多糖類が挙げられる。 Examples of the water-soluble film coating base 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.
　腸溶性フィルムコーティング基剤としては、例えば、ヒドロキシプロピルメチルセルロース　フタレート、ヒドロキシプロピルメチルセルロース　アセテートサクシネート、カルボキシメチルエチルセルロース、酢酸フタル酸セルロース等のセルロース系高分子；メタアクリル酸コポリマーＬ〔オイドラギットＬ（商品名）〕、メタアクリル酸コポリマーＬＤ〔オイドラギットＬ－３０Ｄ５５（商品名）〕、メタアクリル酸コポリマーＳ〔オイドラギットＳ（商品名）〕等のアクリル酸系高分子；セラック等の天然物が挙げられる。 Examples of 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.
　徐放性フィルムコーティング基剤としては、例えば、エチルセルロース等のセルロース系高分子；アミノアルキルメタアクリレートコポリマーＲＳ〔オイドラギットＲＳ（商品名）〕、アクリル酸エチル－メタクリル酸メチル共重合体懸濁液〔オイドラギットＮＥ（商品名）〕等のアクリル酸系高分子が挙げられる。 Examples of the sustained-release film coating base 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)].
　上記したコーティング基剤は、その２種以上を適宜の割合で混合して用いてもよい。また、コーティングの際に、例えば、酸化チタン、酸化鉄（ＩＩＩ）等のような遮光剤を用いてもよい。 The above-mentioned coating bases may be used by mixing two or more of them in an appropriate ratio. In coating, for example, a light shielding agent such as titanium oxide or iron (III) oxide may be used.
　本発明化合物は、毒性（例、急性毒性、慢性毒性、遺伝毒性、生殖毒性、心毒性、癌原性）が低く、副作用も少なく、哺乳動物（例えば、ヒト、ウシ、ウマ、イヌ、ネコ、サル、マウス、ラット）に対し、各種疾患の予防または治療剤、または診断薬として用いることができる。 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.
　本発明化合物は、優れたグルカゴン拮抗作用を有する。
　本発明化合物は、例えば、グルカゴンの作用を遮断することにより、グルカゴンの機能亢進が関与する状態（例えば、肝からの過剰な糖産生、成長ホルモンの過剰分泌、消化管運動の過剰抑制など）を改善することができる。従って、本発明化合物は、グルカゴン拮抗剤、糖産生抑制剤、グルカゴンの作用亢進が関与する疾患の予防または治療剤等として有用であり得る。 The compound of the present invention has an excellent glucagon antagonism.
The compound of the present invention, for example, 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.
　具体的には、本発明化合物は、肥満症、糖尿病（例、１型糖尿病、２型糖尿病、妊娠糖尿病、肥満型糖尿病）、高脂血症（例、高トリグリセリド血症、高コレステロール血症、低ＨＤＬ血症、食後高脂血症）、高血圧症、心不全、糖尿病合併症［例、神経障害、腎症、網膜症、糖尿病性心筋症、白内障、大血管障害、骨減少症、糖尿病性高浸透圧昏睡、感染症（例、呼吸器感染症、***症、消化器感染症、皮膚軟部組織感染症、下肢感染症）、糖尿病性壊疽、口腔乾燥症、聴覚の低下、脳血管障害、末梢血行障害］、メタボリックシンドローム（高トリグリセライド（ＴＧ）血症、低ＨＤＬコレステロール（ＨＤＬ－Ｃ）血症、高血圧、腹部肥満および耐糖能不全から選ばれる３つ以上を保有する病態）、筋肉減少症などの予防または治療剤として用いることができる。
　この中でも特に、本発明化合物は、肥満症および／または糖尿病の予防または治療剤として有用である。 Specifically, 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.
Among these, the compound of the present invention is particularly useful as an agent for preventing or treating obesity and / or diabetes.
　糖尿病の判定基準については、１９９９年に日本糖尿病学会から新たな判定基準が報告されている。 Regarding the criteria for determining diabetes, a new criterion was reported in 1999 by the Japan Diabetes Society.
　この報告によれば、糖尿病とは、空腹時血糖値（静脈血漿におけるグルコース濃度）が１２６ｍｇ／ｄｌ以上、７５ｇ経口ブドウ糖負荷試験（７５ｇＯＧＴＴ）２時間値（静脈血漿におけるグルコース濃度）が２００ｍｇ／ｄｌ以上、随時血糖値（静脈血漿におけるグルコース濃度）が２００ｍｇ／ｄｌ以上のいずれかを示す状態である。また、上記糖尿病に該当せず、かつ、「空腹時血糖値（静脈血漿におけるグルコース濃度）が１１０ｍｇ／ｄｌ未満または７５ｇ経口ブドウ糖負荷試験（７５ｇＯＧＴＴ）２時間値（静脈血漿におけるグルコース濃度）が１４０ｍｇ／ｄｌ未満を示す状態」（正常型）でない状態を、「境界型」と呼ぶ。 According to this report, 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. This is a state in which the blood glucose level (glucose concentration in venous plasma) is at least 200 mg / dl as needed. In addition, it does not correspond to the above-mentioned diabetes, and “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”.
　また、糖尿病の判定基準については、１９９７年にＡＤＡ（米国糖尿病学会）から、１９９８年にＷＨＯから、新たな判定基準が報告されている。 In addition, as for the criteria for determining diabetes, new criteria were reported from ADA (American Diabetes Association) in 1997 and from WHO in 1998.
　これらの報告によれば、糖尿病とは、空腹時血糖値（静脈血漿におけるグルコース濃度）が１２６ｍｇ／ｄｌ以上であり、かつ、７５ｇ経口ブドウ糖負荷試験２時間値（静脈血漿におけるグルコース濃度）が２００ｍｇ／ｄｌ以上を示す状態である。 According to these reports, 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.
　また、上記報告によれば、耐糖能不全とは、空腹時血糖値（静脈血漿におけるグルコース濃度）が１２６ｍｇ／ｄｌ未満であり、かつ、７５ｇ経口ブドウ糖負荷試験２時間値（静脈血漿におけるグルコース濃度）が１４０ｍｇ／ｄｌ以上２００ｍｇ／ｄｌ未満を示す状態である。さらに、ＡＤＡの報告によれば、空腹時血糖値（静脈血漿におけるグルコース濃度）が１１０ｍｇ／ｄｌ以上１２６ｍｇ／ｄｌ未満の状態をＩＦＧ（Impaired Fasting Glucose）と呼ぶ。一方、ＷＨＯの報告によれば、該ＩＦＧ（Impaired Fasting Glucose）のうち、７５ｇ経口ブドウ糖負荷試験２時間値（静脈血漿におけるグルコース濃度）が１４０ｍｇ／ｄｌ未満である状態をＩＦＧ（Impaired Fasting Glycemia）と呼ぶ。 According to the above report, 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). On the other hand, according to the report of WHO, the IFG (Impaired Fasting Glucose) 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.
　本発明化合物は、上記した新たな判定基準により決定される糖尿病、境界型、耐糖能不全、ＩＦＧ（Impaired Fasting Glucose）およびＩＦＧ（Impaired Fasting Glycemia）の予防または治療剤としても用いられる。さらに、本発明化合物は、境界型、耐糖能不全、ＩＦＧ（Impaired Fasting Glucose）またはＩＦＧ（Impaired Fasting Glycemia）から糖尿病への進展を防止することもできる。 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.
　さらに、本発明化合物は、骨粗鬆症、悪液質（例、癌性悪液質、結核性悪液質、糖尿病性悪液質、血液疾患性悪液質、内分泌疾患性悪液質、感染症性悪液質、心疾患性悪液質または後天性免疫不全症候群による悪液質）、脂肪肝、多嚢胞性卵巣症候群、腎疾患（例、糖尿病性ネフロパシー、糸球体腎炎、糸球体硬化症、ネフローゼ症候群、高血圧性腎硬化症、末期腎臓疾患）、筋ジストロフィー、心筋梗塞、狭心症、脳血管障害（例、脳梗塞、脳卒中）、虚血、冠動脈疾患、非Ｑ波梗塞（non-Q wave MI）、うっ血性心不全、心室肥大、新不整脈、間欠性跛行、末梢性閉塞性動脈疾患（例、末梢動脈障害）、アルツハイマー病、パーキンソン病、不安症、痴呆症、インスリン抵抗性症候群、シンドロームＸ、高インスリン血症、高インスリン血症における知覚障害、腫瘍（例、白血病、乳癌、前立腺癌、皮膚癌、上皮癌、腺癌）、過敏性腸症候群、急性または慢性下痢、炎症性疾患（例、慢性関節リウマチ、変形性脊椎炎、変形性関節炎、腰痛、痛風、痛風性関節炎、手術または外傷後の炎症、腫脹、神経痛、咽喉頭炎、膀胱炎、肝炎（非アルコール性脂肪性肝炎を含む）、肺炎、膵炎、腸炎、炎症性腸疾患（炎症性大腸疾患を含む）、潰瘍性大腸炎、胃粘膜損傷（アスピリンにより引き起こされた胃粘膜損傷を含む）、ライム病、風疹性関節炎(rubella arthritis)、乾癬性関節炎(psoriatic arthritis)、結膜炎、胃炎、橋本病、慢性活動性肝炎(chronic active hepatitis)、クローン病、滑膜炎、強直性脊椎炎）、小腸粘膜損傷、吸収不良、精巣機能障害、内臓肥満症候群、筋肉減少症、黄斑変性、再生不良貧血、血小板減少症、多発性硬化症、歯周病、ケロイド形成、肺サルコイドーシス、重症筋無力症、ライター症候群、インフルエンザ、脳マラリア、珪肺、骨吸収性疾患（bone resorption disease）、発熱、筋肉痛、多発性骨髄腫に関連する骨疾患、外傷による神経変性疾患、外傷性脳損傷、巨人症、移植片対宿主反応、移植片拒絶反応、皮膚状態（例、瘢痕組織形成、湿疹、アトピー性皮膚炎、接触性皮膚炎、蕁麻疹、強皮症、乾癬）、アレルギーまたは呼吸器疾患（例、喘息、呼吸窮迫症候群、枯草熱、アレルギー性鼻炎、慢性の肺炎症疾患（例、慢性閉塞性肺疾患（ＣＯＰＤ））、自己免疫疾患に関わる炎症（例、全身性エリテマトーデス、アジソン病、多内分泌腺機能低下症候群（polyglandular deficiency syndrome）、グレーブス病）、感染性疾患（例、敗血病、敗血性ショック、細菌性赤痢、ヘリコバクターピロリ）、ウイルス性疾患（例、単純ヘルペスウイルス感染、サイトメガロウイルス感染、エプスタインバーウイルス感染、ヒト免疫不全ウイルス感染、Ａ型、Ｂ型およびＣ型の肝炎ウイルス感染）、血管新生性の疾患（例、固形癌、眼の新血管形成（ocular neovasculization）、血管腫）、浮腫、無痛覚症、疼痛（例、神経筋疼痛、頭痛、癌または手術による疼痛、歯痛、関節痛）、過敏性腸症候群、白血病、中枢神経系疾患（例えば、脳虚血、脳梗塞、脳浮腫等によるもの）、腎線維症、肝線維症、前立腺線維症、肺線維症などの予防または治療剤としても用いることができる。 Furthermore, 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, dementia, insulin resistance syndrome, syndrome X, hyperinsulinemia, high insulin blood Sensory disturbances in, tumors (eg, leukemia, breast cancer, prostate cancer, skin cancer, epithelial cancer, adenocarcinoma), irritable bowel syndrome, acute or chronic diarrhea, inflammatory diseases (eg, rheumatoid arthritis, osteoarthritis, Osteoarthritis, low back pain, gout, gouty arthritis, inflammation after surgery or trauma, swelling, neuralgia, sore throat, cystitis, hepatitis (including non-alcoholic steatohepatitis), pneumonia, pancreatitis, enteritis, inflammatory Bowel disease (including inflammatory bowel disease), ulcerative colitis, gastric mucosal damage (including gastric mucosal damage caused by aspirin), Lyme disease, rubella arthritis, psoriatic arthritis , Conjunctivitis, gastritis, Hashimoto's disease, chronic active hepatitis, Crohn's disease, synovitis, ankylosing spondylitis), small intestinal mucosal damage, malabsorption, testicular dysfunction, visceral obesity syndrome, muscle loss, Macular degeneration, re Aplastic anemia, thrombocytopenia, multiple sclerosis, periodontal disease, keloid formation, pulmonary sarcoidosis, myasthenia gravis, Reiter syndrome, influenza, brain malaria, silicosis, bone resorption disease, fever, muscle Pain, bone disease associated with multiple myeloma, neurodegenerative disease due to trauma, traumatic brain injury, giantism, graft versus host reaction, graft rejection, skin condition (eg, scar tissue formation, eczema, atopic) Dermatitis, contact dermatitis, hives, scleroderma, psoriasis), allergy or respiratory disease (eg, asthma, respiratory distress syndrome, hay fever, allergic rhinitis, chronic pulmonary inflammatory disease (eg, chronic obstructive) Lung disease (COPD), inflammation associated with autoimmune disease (eg, systemic lupus erythematosus, Addison's disease, polyglandulargdeficiency syndrome, Graves' disease), feeling Sex diseases (eg, septic disease, septic shock, bacterial dysentery, Helicobacter pylori), viral diseases (eg, herpes simplex virus infection, cytomegalovirus infection, Epstein-Barr virus infection, human immunodeficiency virus infection, type A , B and C hepatitis virus infections), angiogenic diseases (eg, solid tumors, ocular neovasculization, hemangiomas), edema, analgesia, pain (eg, neuromuscular pain) , Headache, pain due to cancer or surgery, toothache, joint pain), irritable bowel syndrome, leukemia, central nervous system disease (eg, due to cerebral ischemia, cerebral infarction, cerebral edema, etc.), renal fibrosis, liver fibrosis It can also be used as a prophylactic or therapeutic agent for prostate fibrosis, pulmonary fibrosis and the like.
　さらに、本発明化合物は、消化器運動機能改善剤としても用いることができる。
　本発明化合物は、上記した各種疾患の２次予防および進展抑制（例、心筋梗塞等の心血管イベントの２次予防および進展抑制）にも用いられる。 Furthermore, 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).
　本発明化合物の投与対象は特に限定されないが、哺乳動物（例えば、マウス、ラット、ハムスター、ウサギ、ネコ、イヌ、ウシ、ヒツジ、サル、ヒトなど）が好ましい。
　本発明化合物の投与量は、投与対象、投与ルート、対象疾患、症状等によっても異なるが、例えば、成人の糖尿病患者に経口投与する場合、通常１回量として約０．０１～１００ｍｇ／ｋｇ体重、好ましくは０．０５～３０ｍｇ／ｋｇ体重、さらに好ましくは０．５～１０ｍｇ／ｋｇ体重であり、この量を１日１回～３回投与するのが望ましい。 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.
　本発明化合物は、本発明化合物の作用の増強、本発明化合物の使用量の低減、合併症の予防・治療、生命予後改善等を目的として、本発明化合物に悪影響を及ぼさない併用薬剤と併用することができる。このような併用薬剤としては、例えば、「糖尿病治療薬」、「糖尿病合併症治療薬」、「抗肥満薬」、「高血圧治療薬」、「高脂血症治療薬」、「抗動脈硬化薬」、「抗血栓薬」、「利尿剤」等が挙げられる。これらの併用薬剤は低分子有機化合物であってもよいし、タンパク質、ポリペプチド、抗体、ワクチンなどの高分子であってもよい。 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. Examples of such 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.
　上記「糖尿病治療薬」としては、例えば、インスリン製剤（例、ウシ、ブタの膵臓から抽出された動物インスリン製剤；大腸菌、イーストを用い遺伝子工学的に合成したヒトインスリン製剤；インスリン亜鉛；プロタミンインスリン亜鉛；インスリンのフラグメントまたは誘導体（例、INS-1）、経口インスリン製剤）、インスリン抵抗性改善剤（例、ピオグリタゾンまたはその塩（好ましくは、塩酸塩）、ロシグリタゾンまたはその塩（好ましくは、マレイン酸塩）、メタグリダセン（Metaglidasen）、AMG-131、バラグリタゾン（Balaglitazone）、MBX-2044、リボグリタゾン（Rivoglitazone）、アレグリタザール（Aleglitazar）、チグリタザール（Chiglitazar）、ロベグリタゾン（Lobeglitazone）、PLX-204、PN-2034、GFT-505、THR-0921、WO2007/013694、WO2007/018314、WO2008/093639またはWO2008/099794記載の化合物）、α－グルコシダーゼ阻害剤（例、ボグリボース、アカルボース、ミグリトール、エミグリテート）、ビグアナイド剤（例、メトホルミン、ブホルミンまたはそれらの塩（例、塩酸塩、フマル酸塩、コハク酸塩））、インスリン分泌促進剤（例、スルホニルウレア剤（例、トルブタミド、グリベンクラミド、グリクラジド、クロルプロパミド、トラザミド、アセトヘキサミド、グリクロピラミド、グリメピリド、グリピザイド、グリブゾール）、レパグリニド、ナテグリニド、ミチグリニドまたはそのカルシウム塩水和物）、ジペプチジルペプチダーゼＩＶ阻害剤（例、アログリプチン（Alogliptin）またはその塩（好ましくは、安息香酸塩）、ヴィルダグリプチン（Vildagliptin）、シタグリプチン（Sitagliptin）、サクサグリプチン（Saxagliptin）、BI1356、GRC8200、MP-513、PF-00734200、PHX1149、SK-0403、ALS2-0426、TA-6666、TS-021、KRP-104、2-[[6-[(3R)-3-アミノ-1-ピペリジニル]-3,4-ジヒドロ-3-メチル-2,4-ジオキソ-1(2H)-ピリミジニル]メチル]-4-フルオロベンゾニトリルまたはその塩）、β３アゴニスト（例、N-5984）、GPR40アゴニスト（例、WO2004/041266、WO2004/106276、WO2005/063729、WO2005/063725、WO2005/087710、WO2005/095338、WO2007/013689またはWO2008/001931記載の化合物）、GLP-1受容体アゴニスト（例、GLP-1、GLP-1MR剤、リラグルチド（Liraglutide）、エキセナチド（Exenatide）、AVE-0010、BIM-51077、Aib(8，35)hGLP-1(7,37)NH2、CJC-1131、Albiglutide）、アミリンアゴニスト（例、プラムリンチド）、ホスホチロシンホスファターゼ阻害剤（例、バナジン酸ナトリウム）、糖新生阻害剤（例、グリコーゲンホスホリラーゼ阻害剤、グルコース-6-ホスファターゼ阻害剤、FBPase阻害薬）、SGLT2（sodium-glucose cotransporter 2）阻害剤（例、Depagliflozin、AVE2268、TS-033、YM543、TA-7284、Remogliflozin、ASP1941）、SGLT1阻害薬、11β-ヒドロキシステロイドデヒドロゲナーゼ阻害薬（例、BVT-3498、INCB-13739）、アジポネクチンまたはその作動薬、IKK阻害薬（例、AS-2868）、レプチン抵抗性改善薬、ソマトスタチン受容体作動薬、グルコキナーゼ活性化薬（例、Piragliatin、AZD1656、AZD6370、TTP-355、WO2006/112549、WO2007/028135、WO2008/047821、WO2008/050821、WO2008/136428またはWO2008/156757記載の化合物）、GIP（Glucose-dependent insulinotropic peptide）、GPR119アゴニスト（例、PSN821）、FGF21、FGFアナログ等が挙げられる。 Examples of the “diabetes therapeutic agent” include, for example, 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), α-glucosidase inhibitors (eg, voglibose, acarbose, miglitol, emiglitate), biguanides (eg, metformin, buformin or salts thereof (eg, hydrochloride, fumarate, succinate) )), Insulin secretagogues (eg, sulfonylureas (eg, tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, glybazole), repaglinide, nateglinide, mitiglinide or calcium thereof Salt hydrate), dipeptidyl peptidase IV inhibitor (eg, alogliptin or a salt thereof (preferably benzoate), vildagliptin, sitagliptin, saxag) Lipaxin (Saxagliptin), BI1356, GRC8200, MP-513, PF-00734200, PHX1149, SK-0403, ALS2-0426, TA-6666, TS-021, KRP-104, 2-[[6-[(3R)- 3-amino-1-piperidinyl] -3,4-dihydro-3-methyl-2,4-dioxo-1 (2H) -pyrimidinyl] methyl] -4-fluorobenzonitrile or a salt thereof), β3 agonist (eg, N-5984), GPR40 agonist (eg, compounds described in WO2004 / 041266, WO2004 / 106276, WO2005 / 063729, WO2005 / 063725, WO2005 / 087710, WO2005 / 095338, WO2007 / 013689 or WO2008 / 001931), GLP-1 receptor Body agonists (eg, GLP-1, GLP-1MR agents, Liraglutide, Exenatide, AVE-0010, BIM-51077, Aib (8,35) hGLP-1 (7,37) NH 2 , CJC -1131, Albiglutide), amylin agonist (eg, pramlintide), phosphotyrosine phosphatase inhibitor (eg, sodium vanadate), gluconeogenesis inhibitor (eg, glycogen phosphorylase inhibitor), Lucose-6-phosphatase inhibitor, FBPase inhibitor), SGLT2 (sodium-glucose cotransporter 2) inhibitor (eg, Depagliflozin, AVE2268, TS-033, YM543, TA-7284, Remogliflozin, ASP1941), SGLT1 inhibitor, 11β -Hydroxysteroid dehydrogenase inhibitors (eg, BVT-3498, INCB-13739), adiponectin or agonists thereof, IKK inhibitors (eg, AS-2868), leptin resistance improvers, somatostatin receptor agonists, glucokinase activity Chemicals (eg, Piragliatin, AZD1656, AZD6370, TTP-355, WO2006 / 112549, WO2007 / 028135, WO2008 / 047821, WO2008 / 050821, WO2008 / 136428 or WO2008 / 156757), GIP (Glucose-dependent insulinotropic peptide ), GPR119 agonist (eg, PSN821), FGF21, FGF analog and the like.
　上記「糖尿病合併症治療薬」としては、例えば、アルドース還元酵素阻害剤（例、トルレスタット、エパルレスタット、ゾポルレスタット、フィダレスタット、CT-112、ラニレスタット（AS-3201）、リドレスタット）、神経栄養因子およびその増加薬（例、NGF、NT-3、BDNF、WO01/14372に記載のニューロトロフィン産生・分泌促進剤（例、4-(4-クロロフェニル)-2-(2-メチル-1-イミダゾリル)-5-[3-(2-メチルフェノキシ)プロピル]オキサゾール）、WO2004/039365記載の化合物）、PKC阻害剤（例、ルボキシスタウリン　メシレート（ruboxistaurin mesylate））、AGE阻害剤（例、ALT946、N-フェナシルチアゾリウム　ブロマイド（ALT766）、EXO-226、ピリドリン（Pyridorin）、ピリドキサミン）、GABA受容体作動薬（例、ギャバペンチン、プレギャバリン）、セロトニン・ノルアドレナリン再取込み阻害薬（例、デュロキセチン）、ナトリウムチャンネル阻害薬（例、ラコサミド）、活性酸素消去薬（例、チオクト酸）、脳血管拡張剤（例、チアプリド、メキシレチン）、ソマトスタチン受容体作動薬（例、BIM23190）、アポトーシスシグナルレギュレーティングキナーゼ－１（ASK-1）阻害薬等が挙げられる。 Examples of the above-mentioned “diabetic complication therapeutic agent” 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 receptor agonist (eg, gabapentin, pregabalin), serotonin norad Narine reuptake inhibitors (eg, duloxetine), sodium channel inhibitors (eg, lacosamide), active oxygen scavengers (eg, thioctic acid), cerebral vasodilators (eg, thiaprid, mexiletine), somatostatin receptor agonists (eg, Examples include BIM23190), apoptosis signal regulating kinase-1 (ASK-1) inhibitor, and the like.
　上記「抗肥満薬」としては、例えば、モノアミン取り込み阻害薬（例、フェンテルミン、シブトラミン、マジンドール、フロキセチン、テソフェンシン）、セロトニン2C受容体作動薬(例、ロルカセリン)、セロトニン6受容体拮抗薬、ヒスタミンH3受容体、GABA調節薬（例、トピラメイト）、ニューロペプチドＹ拮抗薬（例、ベルネペリット）、カンナビノイド受容体拮抗薬（例、リモナバン、タラナバン）、グレリン拮抗薬、グレリン受容体拮抗薬、グレリンアシル化酵素阻害薬、オピオイド受容体拮抗薬（例、GSK-1521498）、オレキシン受容体拮抗薬、メラノコルチン4受容体作動薬、11β-ヒドロキシステロイドデヒドロゲナーゼ阻害薬（例、AZD-4017）、膵リパーゼ阻害薬（例、オルリスタット、セティリスタット（cetilistat））、β3アゴニスト（例、N-5984）、ジアシルグリセロールアシルトランスフェラーゼ1（DGAT1）阻害薬、アセチルCoAカルボキシラーゼ（ACC）阻害薬、ステアリン酸CoA脱飽和酵素阻害薬、ミクロソームトリグリセリド転送蛋白阻害薬（例、R-256918）、Na-グルコース共輸送担体阻害薬（例、ＪNJ-28431754、レモグリフロジン）、NFκ阻害薬（例、HE-3286）、PPARアゴニスト（例、GFT-505、DRF-11605）、ホスホチロシンホスファターゼ阻害剤（例、バナジン酸ナトリウム、トロダスケミン（Trodusquemin））、GPR119作動薬（例、PSN-821）、グルコキナーゼ活性化薬（例、AZD-1656）、メラニン凝集ホルモン（MCH）受容体拮抗薬（例、SB-568849、SNAP-7941、WO01/82925およびWO01/87834に記載の化合物）、レプチン、レプチン誘導体（例、メトレレプチン）、CNTF（毛様体神経栄養因子）、BDNF（脳由来神経栄養因子）、コレシストキニンアゴニスト、グルカゴン様ペプチド-1（GLP-1）製剤（例、ウシ、ブタの膵臓から抽出された動物GLP-1製剤；大腸菌、イーストを用い遺伝子工学的に合成したヒトGLP-1製剤；GLP-1のフラグメントまたは誘導体（例、エクセナチド、リラグルチド））、アミリン製剤（例、プラムリンタイド、AC-2307）、ニューロペプチドYアゴニスト（例、PYY3-36、PYY3-36の誘導体、オビネプタイド、TM-30339、TM-30335）、オキシントモジュリン製剤：FGF21製剤（例、ウシ、ブタの膵臓から抽出された動物FGF21製剤；大腸菌、イーストを用い遺伝子工学的に合成したヒトFGF21製剤；FGF21のフラグメントまたは誘導体）、摂食抑制薬（例、P-57）等が挙げられる。 Examples of the above “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, 11β-hydroxysteroid dehydrogenase inhibitors (eg, AZD-4017), pancreatic lipase inhibitors (Eg, orlistat, cetilistat), β3 agonist ( Eg, N-5984), diacylglycerol acyltransferase 1 (DGAT1) inhibitor, acetyl CoA carboxylase (ACC) inhibitor, stearate CoA desaturase inhibitor, microsomal triglyceride transfer protein inhibitor (eg, R-256918), Na-glucose co-transport carrier inhibitor (eg, JNJ-28431754, remogliflozin), NFκ inhibitor (eg, HE-3286), PPAR agonist (eg, GFT-505, DRF-11605), phosphotyrosine phosphatase inhibitor (eg, Sodium vanadate, Trodusquemin), GPR119 agonist (eg, PSN-821), glucokinase activator (eg, AZD-1656), melanin-concentrating hormone (MCH) receptor antagonist (eg, SB-568849) , SNAP-7941, compounds described in WO01 / 82925 and WO01 / 87834), leptin, leptin derivatives (eg, metreleptin), CNTF (ciliary neurotrophic factor), BDNF (brain-derived neuroproliferation) Factor), cholecystokinin agonist, glucagon-like peptide-1 (GLP-1) preparation (eg, animal GLP-1 preparation extracted from bovine and porcine pancreas; human GLP synthesized by genetic engineering using Escherichia coli and yeast -1 preparations; GLP-1 fragments or derivatives (eg, exenatide, liraglutide)), amylin preparations (eg, pramlintide, AC-2307), neuropeptide Y agonists (eg, PYY3-36, PYY3-36 derivatives) , Obineptide, TM-30339, TM-30335), oxyntomodulin preparation: FGF21 preparation (eg, animal FGF21 preparation extracted from bovine and porcine pancreas; human FGF21 preparation synthesized by genetic engineering using Escherichia coli and yeast; FGF21 fragment or derivative), antifeedant (eg, P-57) and the like.
　上記「高血圧治療薬」としては、例えば、アンジオテンシン変換酵素阻害剤（例、カプトプリル、エナラプリル、デラプリル）、アンジオテンシンII拮抗剤（例、カンデサルタン　シレキセチル、カンデサルタン、ロサルタン、ロサルタン　カリウム、エプロサルタン、バルサルタン、テルミサルタン、イルベサルタン、タソサルタン、オルメサルタン、オルメサルタン　メドキソミル、アジルサルタン、アジルサルタン　メドキソミル）、カルシウム拮抗剤（例、マニジピン、ニフェジピン、アムロジピン、エホニジピン、ニカルジピン、シニルジピン）、βブロッカー（例、メトプロロール、アテノロール、プロプラノロール、カルベジロール、ピンドロール）、クロニジン等が挙げられる。 Examples of the “antihypertensive agent” include an 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), β-blockers (eg, metoprolol, atenolol carprololol, prodrolol, ), Clonidine and the like.
　上記「高脂血症治療薬」としては、例えば、HMG-CoA還元酵素阻害剤（例、プラバスタチン、シンバスタチン、ロバスタチン、アトルバスタチン、フルバスタチン、ロスバスタチン、ピタバスタチンまたはそれらの塩（例、ナトリウム塩、カルシウム塩））、スクアレン合成酵素阻害剤（例、WO97/10224記載の化合物、例えば、N-[[(3R,5S)-1-(3-アセトキシ-2,2-ジメチルプロピル)-7-クロロ-5-(2，3-ジメトキシフェニル)-2-オキソ-1,2,3,5-テトラヒドロ-4,1-ベンゾオキサゼピン-3-イル]アセチル]ピペリジン-4-酢酸）、フィブラート系化合物（例、ベザフィブラート、クロフィブラート、シムフィブラート、クリノフィブラート）、陰イオン交換樹脂（例、コレスチラミン）、プロブコール、ニコチン酸系薬剤（例、ニコモール（nicomol）、ニセリトロール（niceritrol）、ナイアスパン（niaspan））、イコサペント酸エチル、植物ステロール（例、ソイステロール（soysterol）、ガンマオリザノール（γ-oryzanol））、コレステロール吸収阻害剤 (例、ゼチア)、CETP阻害剤(例、ダルセトラピブ（dalcetrapib）、アナセトラピブ（anacetrapib））、ω-3脂肪酸製剤（例、ω-3-acid ethyl esters 90）等が挙げられる。 Examples of the “hyperlipidemic agent” 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, cholestyramine), probucol, nicotinic acid drugs (eg, nicomol, niceritr) ol), niaspan), ethyl icosapentate, plant sterols (eg, soysterol, gamma-oryzanol), cholesterol absorption inhibitors (eg, zetia), CETP inhibitors (eg, dalcetrapib) (Dalcetrapib), anacetrapib), ω-3 fatty acid preparations (eg, ω-3-acid ethyl esters 90) and the like.
　上記「抗動脈硬化薬」としては、例えば、アシルコエンザイムＡコレステロールアシル転移酵素（ACAT）阻害剤（例、K-604)、LpPLA2阻害薬（例、ダラプラディブ、リラプラディブ）、FLAP阻害薬(例、AM103、AM803)、5LO阻害薬（例、VIA-2291）、sPLA2阻害薬（例、A-002）、apoAIミメティックペプチド（例、D4F）、HDL製剤（例、CSL-111）等が挙げられる。 Examples of the above “anti-arteriosclerotic agent” 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.
　上記「抗血栓薬」としては、例えば、ヘパリン（例、ヘパリンナトリウム、ヘパリンカルシウム、エノキサパリンナトリウム(enoxaparin sodium)、ダルテパリンナトリウム(dalteparin sodium)）、ワルファリン（例、ワルファリンカリウム）、抗トロンビン薬（例、アルガトロバン(aragatroban)、ダビガトラン(dabigatran)）、FXa阻害薬（例、リバロキサバン(rivaroxaban)、アピキサバン(apixaban)、エドキサバン(edoxaban)、YM150、WO02/06234、WO2004/048363、WO2005/030740、WO2005/058823またはWO2005/113504記載の化合物）、血栓溶解薬（例、ウロキナーゼ(urokinase)、チソキナーゼ(tisokinase)、アルテプラーゼ(alteplase)、ナテプラーゼ(nateplase)、モンテプラーゼ(monteplase)、パミテプラーゼ(pamiteplase)）、血小板凝集抑制薬（例、塩酸チクロピジン(ticlopidine hydrochloride)、クロピドグレル、プラスグレル、E5555、SHC530348、シロスタゾール(cilostazol)、イコサペント酸エチル、ベラプロストナトリウム(beraprost sodium)、塩酸サルポグレラート(sarpogrelate hydrochloride)）等が挙げられる。 Examples of the above-mentioned “antithrombotic agents” 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, alteplase, nateplase, monteplase, pamiteplase), platelet aggregation inhibitor (Eg, ticlopidine hydrochloride, clopidogrel, Excellent, E5555, SHC530348, cilostazol (cilostazol), ethyl icosapentate, beraprost sodium (beraprost sodium), and the like sarpogrelate hydrochloride (sarpogrelate hydrochloride)) is.
　上記「利尿剤」としては、例えば、キサンチン誘導体（例、サリチル酸ナトリウムテオブロミン、サリチル酸カルシウムテオブロミン）、チアジド系製剤（例、エチアジド、シクロペンチアジド、トリクロルメチアジド、ヒドロクロロチアジド、ヒドロフルメチアジド、ベンチルヒドロクロロチアジド、ペンフルチアジド、ポリ５チアジド、メチクロチアジド）、抗アルドステロン製剤（例、スピロノラクトン、トリアムテレン）、炭酸脱水酵素阻害剤（例、アセタゾラミド）、クロルベンゼンスルホンアミド系製剤（例、クロルタリドン、メフルシド、インダパミド）、アゾセミド、イソソルビド、エタクリン酸、ピレタニド、ブメタニド、フロセミドなどが挙げられる。 Examples of the above “diuretic” include 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.
　前記した併用薬剤の投与時期は限定されず、本発明化合物と併用薬剤とを、投与対象に対し、同時に投与してもよいし、時間差をおいて投与してもよい。併用薬剤の投与量は、臨床上用いられている投与量に準ずればよく、投与対象、投与ルート、疾患、組み合わせ等により適宜選択することができる。
　併用薬剤の投与形態は、特に限定されず、投与時に、本発明化合物と併用薬剤とが組み合わされていればよい。このような投与形態としては、例えば、１）本発明化合物と併用薬剤とを同時に製剤化して得られる単一の製剤の投与、２）本発明化合物と併用薬剤とを別々に製剤化して得られる２種の製剤の同一投与経路での同時投与、３）本発明化合物と併用薬剤とを別々に製剤化して得られる２種の製剤の同一投与経路での時間差をおいての投与、４）本発明化合物と併用薬剤とを別々に製剤化して得られる２種の製剤の異なる投与経路での同時投与、５）本発明化合物と併用薬剤とを別々に製剤化して得られる２種の製剤の異なる投与経路での時間差をおいての投与（例えば、本発明化合物、併用薬剤の順序での投与、あるいは逆の順序での投与）等が挙げられる。
　本発明化合物と併用薬剤との配合比は、投与対象、投与ルート、疾患等により適宜選択することができる。 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.
　以下に、実施例、実験例および製剤例を挙げて本発明をさらに詳細に説明するが、本発明はこれらにより限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to Examples, Experimental Examples and Preparation Examples, but the present invention is not limited thereto.
　１Ｈ－ＮＭＲスペクトルは、内部基準としてテトラメチルシランを用いてバリアンジェミニ３００（３００ＭＨｚ）型、ブルカー３００（３００ＭＨｚ）スペクトルメーターで測定し、全δ値をｐｐｍで示した。混合溶媒において示した数値は、特に断らない限り各溶媒の容量混合比である。％は、特に断らない限り重量％を意味する。またシリカゲルクロマトグラフィーにおける溶出溶媒の比は、特に断らない限り容量比を示す。本明細書中における室温（常温）とは約２０℃から約３０℃の温度を表す。 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 δ 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.
　なお、実施例中の各記号は次の意味を表す。
ＤＭＳＯ：ジメチルスルホキシド、
ＣＤＣｌ３：重クロロホルム、
ｓ：シングレット、
ｄ：ダブレット、
ｔ：トリプレット、
ｑ：クアルテット、
ｄｄ：ダブルダブレット、
ｄｔ：ダブルトリプレット、
ｑｕｉｎｔ：クインテット、
ｍ：マルチプレット、
ｂｒ　ｓ：幅広いシングレット、
Ｊ：カップリング定数 In addition, 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は以下の装置・条件で測定した。
装置：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
カラム：ZORBAX Extend-C18 Rapid Resolution HT
　　　　(3.0×30 mm 1.8 micron 600 bar)
移動相：A：Ultra Pure Water (10 mM AcONH4)
　　　　B：MeCN (10 mM AcONH4)
Gradient：0.00 min (A/B=90/10), 0.20 min (A/B=90/10), 1.50 min (A/B=0/100), 2.00 min (A/B=0/100)
流速：1.2 ml/min
検出：UV 220 mm
温度：40℃ 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
Column: ZORBAX Extend-C18 Rapid Resolution HT
(3.0 × 30 mm 1.8 micron 600 bar)
Mobile phase: A: Ultra Pure Water (10 mM AcONH 4 )
B: MeCN (10 mM AcONH 4 )
Gradient: 0.00 min (A / B = 90/10), 0.20 min (A / B = 90/10), 1.50 min (A / B = 0/100), 2.00 min (A / B = 0/100)
Flow rate: 1.2 ml / min
Detection: UV 220 mm
Temperature: 40 ° C
実施例１
3-{[(6-{[シクロヘキシル(5-フルオロ-1-メチル-1H-インドール-2-イル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸 Example 1
3-{[(6-{[Cyclohexyl (5-fluoro-1-methyl-1H-indol-2-yl) methyl] amino} pyridin-3-yl) carbonyl] (methyl) amino} propanoic acid
Figure JPOXMLDOC01-appb-C000001
Figure JPOXMLDOC01-appb-C000001
（１）(5-フルオロ-1H-インドール-2-イル)メタノール
　テトラヒドロフラン（５０ｍＬ）に０℃で水素化アルミニウムリチウム（８４３ｍｇ）を加えた。続いて５-フルオロ-１H-インドール-２-カルボン酸エチル（５．００ｇ）のテトラヒドロフラン（１０ｍＬ）溶液を０℃で加えた。混合物を０℃で３０分撹拌した。反応混合物に硫酸ナトリウム十水和物（１１．６ｇ）を加え、室温で４時間撹拌した。不溶物をろ過により除いた後、ろ液を減圧下濃縮し、標記目的化合物（３．３５ｇ，８４％）を無色固体として得た。
1H NMR (300 MHz, CDCl3) δ ppm 2.33 (br s, 1 H), 4.77 (br s, 2 H), 6.33 (s, 1 H), 6.91 (td, J=9.1, 2.3 Hz, 1 H), 7.09 - 7.24 (m, 2 H), 8.49 (br s, 1 H)． (1) (5-Fluoro-1H-indol-2-yl) methanol Lithium aluminum hydride (843 mg) was added to tetrahydrofuran (50 mL) at 0 ° C. Subsequently, a solution of ethyl 5-fluoro-1H-indole-2-carboxylate (5.00 g) in tetrahydrofuran (10 mL) was added at 0 ° C. The mixture was stirred at 0 ° C. for 30 minutes. Sodium sulfate decahydrate (11.6 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 4 hr. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title object compound (3.35 g, 84%) as a colorless solid.
1 H NMR (300 MHz, CDCl 3 ) δ ppm 2.33 (br s, 1 H), 4.77 (br s, 2 H), 6.33 (s, 1 H), 6.91 (td, J = 9.1, 2.3 Hz, 1 H), 7.09-7.24 (m, 2 H), 8.49 (br s, 1 H).
（２）5-フルオロ-1H-インドール-2-カルバルデヒド
　(5-フルオロ-1H-インドール-2-イル)メタノール（３．３５ｇ）と活性二酸化マンガン（１５．０ｇ）とテトラヒドロフラン（３０ｍＬ）の混合物を５０℃で１６時間撹拌した。二酸化マンガンをろ過により除去した後、ろ液を減圧下濃縮し、標記目的化合物（３．０４ｇ，９２％）を褐色固体として得た。
1H NMR (300 MHz, CDCl3) δ ppm 7.08 - 7.21 (m, 1 H), 7.23 - 7.25 (m, 1 H), 7.33 - 7.45 (m, 2 H), 9.26 (br s, 1 H), 9.85 (s, 1 H)． (2) A mixture of 5-fluoro-1H-indole-2-carbaldehyde (5-fluoro-1H-indol-2-yl) methanol (3.35 g), active manganese dioxide (15.0 g) and tetrahydrofuran (30 mL) Was stirred at 50 ° C. for 16 hours. Manganese dioxide was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title object compound (3.04 g, 92%) as a brown solid.
1 H NMR (300 MHz, CDCl 3 ) δ ppm 7.08-7.21 (m, 1 H), 7.23-7.25 (m, 1 H), 7.33-7.45 (m, 2 H), 9.26 (br s, 1 H) , 9.85 (s, 1 H).
（３）5-フルオロ-1-メチル-1H-インドール-2-カルバルデヒド
　5-フルオロ-1H-インドール-2-カルバルデヒド（３．０４ｇ）のＮ，Ｎ－ジメチルホルムアミド（３０ｍＬ）溶液に０℃で水素化ナトリウム（６０％、油性、８９４ｍｇ）を加え、０℃で１０分間撹拌した。反応液にヨウ化メチル（２．８９ｇ）を０℃で加えた後、０℃で１０分間撹拌した。水を加え反応を停止した後、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。ろ過操作後ろ液を濃縮した。残留物をジイソプロピルエーテル/ヘキサンから結晶化させることで標記目的化合物（２．４１ｇ，７３％）を褐色結晶として得た。
1H NMR (300 MHz, CDCl3) δ ppm 4.09 (s, 3 H), 7.10 - 7.23 (m, 2 H), 7.31 - 7.40 (m, 2 H), 9.88 (s, 1 H)． (3) 5-fluoro-1-methyl-1H-indole-2-carbaldehyde To a solution of 5-fluoro-1H-indole-2-carbaldehyde (3.04 g) in N, N-dimethylformamide (30 mL) at 0 ° C. Sodium hydride (60%, oily, 894 mg) was added and stirred at 0 ° C. for 10 minutes. Methyl iodide (2.89 g) was added to the reaction solution at 0 ° C., followed by stirring at 0 ° C. for 10 minutes. Water was added to stop the reaction, followed by extraction with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The filtrate after the filtration operation was concentrated. The residue was crystallized from diisopropyl ether / hexane to give the title object compound (2.41 g, 73%) as brown crystals.
1 H NMR (300 MHz, CDCl 3 ) δ ppm 4.09 (s, 3 H), 7.10-7.23 (m, 2 H), 7.31-7.40 (m, 2 H), 9.88 (s, 1 H).
（４）6-{[シクロヘキシル(5-フルオロ-1-メチル-1H-インドール-2-イル)メチル]アミノ}ピリジン-3-カルボン酸メチル
　5-フルオロ-1-メチル-1H-インドール-2-カルバルデヒド（２．３９ｇ）のテトラヒドロフラン（４０ｍＬ）溶液に０℃で１．０Ｍシクロヘキシルマグネシウムブロミドのテトラヒドロフラン溶液（１６ｍＬ）を加え、０℃で５分間撹拌した。１規定塩酸水溶液を加え反応を停止した後、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。ろ過操作後、ろ液を濃縮し、残留物をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル１００：０～８０：２０、v/v）で精製し、赤色固体（２．１０ｇ）を得た。得られた赤色固体（２．０５ｇ）と塩化チオニル（６８７μＬ）のテトラヒドロフラン（２０ｍＬ）溶液を室温で２時間撹拌した。反応液に氷と飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。ろ過操作後、ろ液を濃縮し、紫色アモルファス固体（２．０ｇ）を得た。得られた紫色アモルファス固体（１．３ｇ）に6-アミノピリジン-3-カルボン酸メチル（７４２ｍｇ）、ヨウ化ナトリウム（１．３９ｇ）、炭酸ナトリウム（９８３mg）、N,N-ジメチルアセトアミド（１３mL）を加え、８０℃で１７時間撹拌した。反応液に水を加え酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。ろ過操作後、ろ液を濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル100：0～90：10、v/v）に付し、標記目的化合物（４０１ｍｇ，１３％）を黄色アモルファス固体として得た。
1H NMR (300 MHz, CDCl3) δ ppm 1.04 - 1.24 (m, 4 H), 1.67 - 2.01 (m, 7 H), 3.75 (s, 3 H), 3.84 (s, 3 H), 5.01 (d, J=8.7 Hz, 1 H), 5.11 - 5.29 (m, 1 H), 6.28 (d, J=8.7 Hz, 1 H), 6.35 (s, 1 H), 6.92 (td, J=9.1, 2.3 Hz, 1 H), 7.13 - 7.22 (m, 2 H), 7.90 (dd, J=8.7, 2.3 Hz, 1 H), 8.73 (d, J=1.9 Hz, 1 H)． (4) 6-{[cyclohexyl (5-fluoro-1-methyl-1H-indol-2-yl) methyl] amino} pyridine-3-carboxylate methyl 5-fluoro-1-methyl-1H-indole-2- To a solution of carbaldehyde (2.39 g) in tetrahydrofuran (40 mL) was added 1.0 M cyclohexylmagnesium bromide in tetrahydrofuran (16 mL) at 0 ° C., and the mixture was stirred at 0 ° C. for 5 min. 1N Hydrochloric acid aqueous solution was added to stop the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate 100: 0-80: 20, v / v) to obtain a red solid (2.10 g). A solution of the obtained red solid (2.05 g) and thionyl chloride (687 μL) in tetrahydrofuran (20 mL) was stirred at room temperature for 2 hours. Ice and saturated aqueous sodium hydrogen carbonate solution were 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 the filtration operation, the filtrate was concentrated to obtain a purple amorphous solid (2.0 g). To the obtained purple amorphous solid (1.3 g), methyl 6-aminopyridine-3-carboxylate (742 mg), sodium iodide (1.39 g), sodium carbonate (983 mg), N, N-dimethylacetamide (13 mL) And stirred at 80 ° C for 17 hours. Water 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 the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100: 0 to 90:10, v / v) to give the title object compound (401 mg, 13%) as a yellow amorphous solid.
1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.04-1.24 (m, 4 H), 1.67-2.01 (m, 7 H), 3.75 (s, 3 H), 3.84 (s, 3 H), 5.01 ( d, J = 8.7 Hz, 1 H), 5.11-5.29 (m, 1 H), 6.28 (d, J = 8.7 Hz, 1 H), 6.35 (s, 1 H), 6.92 (td, J = 9.1, 2.3 Hz, 1 H), 7.13-7.22 (m, 2 H), 7.90 (dd, J = 8.7, 2.3 Hz, 1 H), 8.73 (d, J = 1.9 Hz, 1 H).
（５）6-{[シクロヘキシル(5-フルオロ-1-メチル-1H-インドール-2-イル)メチル]アミノ}ピリジン-3-カルボン酸
　6-{[シクロヘキシル(5-フルオロ-1-メチル-1H-インドール-2-イル)メチル]アミノ}ピリジン-3-カルボン酸メチル（３９０ｍｇ）および１規定水酸化ナトリウム水溶液（１．９７ｍＬ）のテトラヒドロフラン（４．０ｍＬ）-メタノール（４．０ｍＬ）混合溶液を加熱還流下で２時間撹拌した。反応混合物を減圧下濃縮した後、水（６ｍＬ）を加え、1規定塩酸水溶液（１．９７ｍＬ）で中和した。生成した沈殿物をろ取し、標記目的化合物（３１５ｍｇ，８４％）を無色アモルファス固体として得た。
1H NMR (300 MHz, CDCl3) δ ppm 1.04 - 2.11 (m, 11 H), 3.75 - 3.81 (m, 4 H), 6.28 - 6.42 (m, 2 H), 6.81 - 7.01 (m, 1 H), 7.14 - 7.21 (m, 2 H), 7.95 - 8.03 (m, 1 H), 8.75 (d, J=2.3 Hz, 1 H)． (5) 6-{[cyclohexyl (5-fluoro-1-methyl-1H-indol-2-yl) methyl] amino} pyridine-3-carboxylic acid 6-{[cyclohexyl (5-fluoro-1-methyl-1H -Indol-2-yl) methyl] amino} pyridine-3-carboxylate (390 mg) and 1N aqueous sodium hydroxide solution (1.97 mL) in tetrahydrofuran (4.0 mL) -methanol (4.0 mL) The mixture was stirred for 2 hours under heating to reflux. The reaction mixture was concentrated under reduced pressure, water (6 mL) was added, and the mixture was neutralized with 1N aqueous hydrochloric acid solution (1.97 mL). The resulting precipitate was collected by filtration to give the title object compound (315 mg, 84%) as a colorless amorphous solid.
1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.04-2.11 (m, 11 H), 3.75-3.81 (m, 4 H), 6.28-6.42 (m, 2 H), 6.81-7.01 (m, 1 H ), 7.14-7.21 (m, 2 H), 7.95-8.03 (m, 1 H), 8.75 (d, J = 2.3 Hz, 1 H).
（６）3-{[(6-{[シクロヘキシル(5-フルオロ-1-メチル-1H-インドール-2-イル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸エチル
　6-{[シクロヘキシル(5-フルオロ-1-メチル-1H-インドール-2-イル)メチル]アミノ}ピリジン-3-カルボン酸（３１０ｍｇ）、３－（メチルアミノ）プロパン酸エチル（１３０ｍｇ）、1-ヒドロキシベンゾトリアゾール・１水和物（１５０ｍｇ）、トリエチルアミン（２７３μＬ）、1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド 塩酸塩（１８８ｍｇ）およびN,N-ジメチルホルムアミド（４ｍＬ）の混合物を室温で１４時間撹拌した。飽和塩化アンモニウム水溶液を加え反応を停止した後、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。ろ過操作後、ろ液を濃縮した。残留物をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル１００：０～５０：５０、v/v）で精製し、標記目的化合物（２３４ｍｇ，５９％）を無色アモルファス固体として得た。
1H NMR (300 MHz, CDCl3) δ ppm 1.04 - 1.29 (m, 10 H), 1.62 - 1.75 (m, 4 H), 2.64 (t, J=7.0 Hz, 2 H), 3.06 (s, 3 H), 3.64 - 3.77 (m, 5 H), 4.04 - 4.21 (m, 2 H), 4.83 (d, J=8.3 Hz, 1 H), 5.09 (t, J=8.3 Hz, 1 H), 6.28 (d, J=8.7 Hz, 1 H), 6.35 (s, 1 H), 6.92 (td, J=9.1, 2.3 Hz, 1 H), 7.15 - 7.23 (m, 2 H), 7.45 (dd, J=8.5, 2.5 Hz, 1 H), 8.20 (d, J=1.9 Hz, 1 H)． (6) 3-{[(6-{[Cyclohexyl (5-fluoro-1-methyl-1H-indol-2-yl) methyl] amino} pyridin-3-yl) carbonyl] (methyl) amino} propanoic acid ethyl 6-{[cyclohexyl (5-fluoro-1-methyl-1H-indol-2-yl) methyl] amino} pyridine-3-carboxylic acid (310 mg), ethyl 3- (methylamino) propanoate (130 mg), 1 A mixture of -hydroxybenzotriazole monohydrate (150 mg), triethylamine (273 μL), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (188 mg) and N, N-dimethylformamide (4 mL) Stir at room temperature for 14 hours. Saturated aqueous ammonium chloride solution was added to stop the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate 100: 0-50: 50, v / v) to give the title object compound (234 mg, 59%) as a colorless amorphous solid.
1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.04-1.29 (m, 10 H), 1.62-1.75 (m, 4 H), 2.64 (t, J = 7.0 Hz, 2 H), 3.06 (s, 3 H), 3.64-3.77 (m, 5 H), 4.04-4.21 (m, 2 H), 4.83 (d, J = 8.3 Hz, 1 H), 5.09 (t, J = 8.3 Hz, 1 H), 6.28 (d, J = 8.7 Hz, 1 H), 6.35 (s, 1 H), 6.92 (td, J = 9.1, 2.3 Hz, 1 H), 7.15-7.23 (m, 2 H), 7.45 (dd, J = 8.5, 2.5 Hz, 1 H), 8.20 (d, J = 1.9 Hz, 1 H).
（７）3-{[(6-{[シクロヘキシル(5-フルオロ-1-メチル-1H-インドール-2-イル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸
　3-{[(6-{[シクロヘキシル(5-フルオロ-1-メチル-1H-インドール-2-イル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸エチル（２２０ｍｇ）と1規定水酸化ナトリウム水溶液（９００μＬ）のエタノール（２．０ｍＬ）-テトラヒドロフラン（２．０ｍＬ）混合溶液を室温で１．５時間撹拌した。溶媒を減圧留去した後に、水（４．０ｍＬ）を加え、１規定塩酸水溶液（９００μＬ）で中和した。生成した沈殿物をろ取することで標記目的化合物（１７２ｍｇ，８２％）を無色アモルファス固体として得た。
1H NMR (300 MHz, CDCl3) δ ppm 1.09 - 2.17 (m, 11 H), 2.63 (t, J=5.5 Hz, 2 H), 3.05 (s, 3 H), 3.67 - 3.80 (m, 5 H), 4.53 (br s, 1 H), 6.41 (s, 1 H), 6.49 (d, J=9.0 Hz, 1 H), 6.92 (td, J=9.0, 2.6 Hz, 1 H), 7.12 - 7.22 (m, 2 H), 7.57 (dd, J=8.9, 1.7 Hz, 1 H), 8.05 (br s, 1 H)．
HPLC-MS:m/z=467.5(M+1); Rt=1.00 min (7) 3-{[(6-{[Cyclohexyl (5-fluoro-1-methyl-1H-indol-2-yl) methyl] amino} pyridin-3-yl) carbonyl] (methyl) amino} propanoic acid 3 -{[(6-{[cyclohexyl (5-fluoro-1-methyl-1H-indol-2-yl) methyl] amino} pyridin-3-yl) carbonyl] (methyl) amino} ethyl propanoate (220 mg) A 1N aqueous solution of sodium hydroxide (900 μL) in ethanol (2.0 mL) -tetrahydrofuran (2.0 mL) was stirred at room temperature for 1.5 hours. After the solvent was distilled off under reduced pressure, water (4.0 mL) was added and neutralized with a 1N aqueous hydrochloric acid solution (900 μL). The resulting precipitate was collected by filtration to give the title object compound (172 mg, 82%) as a colorless amorphous solid.
1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.09-2.17 (m, 11 H), 2.63 (t, J = 5.5 Hz, 2 H), 3.05 (s, 3 H), 3.67-3.80 (m, 5 H), 4.53 (br s, 1 H), 6.41 (s, 1 H), 6.49 (d, J = 9.0 Hz, 1 H), 6.92 (td, J = 9.0, 2.6 Hz, 1 H), 7.12- 7.22 (m, 2 H), 7.57 (dd, J = 8.9, 1.7 Hz, 1 H), 8.05 (br s, 1 H).
HPLC-MS: m / z = 467.5 (M + 1); Rt = 1.00 min
実施例２
3-{[(6-{[シクロヘキシル(5-フルオロ-1-メチル-1H-インドール-2-イル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸 Example 2
3-{[(6-{[Cyclohexyl (5-fluoro-1-methyl-1H-indol-2-yl) methyl] amino} pyridin-3-yl) carbonyl] (methyl) amino} propanoic acid
Figure JPOXMLDOC01-appb-C000002
Figure JPOXMLDOC01-appb-C000002
　実施例１の（７）で合成した3-{[(6-{[シクロヘキシル(5-フルオロ-1-メチル-1H-インドール-2-イル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸（９８ｍｇ）を高速液体クロマトグラフィー（カラム：ＣＨＩＲＡＬＰＡＫ ＡＤ（５０ｍｍＩＤ×５００ｍｍＬ、ダイセル化学工業製）、移動相：ヘキサン／２－プロパノール／ギ酸（７００／３００／１、ｖ／ｖ／ｖ）、流速：８０ｍＬ／ｍｉｎ、カラム温度：３０℃）を用いて分画した。上記の高速液体クロマトグラフィー条件にて保持時間が２３分から２９分の光学活性体を含有する分画液を飽和炭酸水素ナトリウム水溶液で洗浄した。水層を酢酸エチルで抽出し、有機層を合わせて飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。ろ過操作後、ろ液を濃縮し、標記目的化合物の光学活性体（４２ｍｇ）を無色アモルファス固体として得た。
HPLC-MS:m/z=467.5(M+1); Rt=1.00 min 3-{[(6-{[cyclohexyl (5-fluoro-1-methyl-1H-indol-2-yl) methyl] amino} pyridin-3-yl) carbonyl] () synthesized in (7) of Example 1 Methyl) amino} propanoic acid (98 mg) was subjected to high performance liquid chromatography (column: CHIRALPAK AD (50 mm ID × 500 mmL, manufactured by Daicel Chemical Industries), mobile phase: hexane / 2-propanol / formic acid (700/300/1, v / v) / V), flow rate: 80 mL / min, column temperature: 30 ° C.). A fraction solution containing an optically active substance with a retention time of 23 to 29 minutes under the above-mentioned high performance liquid chromatography conditions was washed with a saturated aqueous solution of sodium bicarbonate. The aqueous layer was extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to obtain the optically active form of the title target compound (42 mg) as a colorless amorphous solid.
HPLC-MS: m / z = 467.5 (M + 1); Rt = 1.00 min
実施例３
3-{[(6-{[シクロヘキシル(5-フルオロ-1-メチル-1H-インドール-2-イル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸 Example 3
3-{[(6-{[Cyclohexyl (5-fluoro-1-methyl-1H-indol-2-yl) methyl] amino} pyridin-3-yl) carbonyl] (methyl) amino} propanoic acid
Figure JPOXMLDOC01-appb-C000003
Figure JPOXMLDOC01-appb-C000003
　実施例１の（７）で合成した3-{[(6-{[シクロヘキシル(5-フルオロ-1-メチル-1H-インドール-2-イル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸（９８ｍｇ）を高速液体クロマトグラフィー（カラム：ＣＨＩＲＡＬＰＡＫ ＡＤ（５０ｍｍＩＤ×５００ｍｍＬ、ダイセル化学工業製）、移動相：ヘキサン／２－プロパノール／ギ酸（７００／３００／１、ｖ／ｖ／ｖ）、流速：８０ｍＬ／ｍｉｎ、カラム温度：３０℃）を用いて分画した。上記の高速液体クロマトグラフィー条件にて保持時間が３６分から４５分の光学活性体を含有する分画液を飽和炭酸水素ナトリウム水溶液で洗浄した。水層を酢酸エチルで抽出し、有機層を合わせて飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。ろ過操作後、ろ液を濃縮し、標記目的化合物の光学活性体（４６ｍｇ）を無色アモルファス固体として得た。
HPLC-MS:m/z=467.3(M+1); Rt=1.00 min 3-{[(6-{[cyclohexyl (5-fluoro-1-methyl-1H-indol-2-yl) methyl] amino} pyridin-3-yl) carbonyl] () synthesized in (7) of Example 1 Methyl) amino} propanoic acid (98 mg) was subjected to high performance liquid chromatography (column: CHIRALPAK AD (50 mm ID × 500 mmL, manufactured by Daicel Chemical Industries), mobile phase: hexane / 2-propanol / formic acid (700/300/1, v / v) / V), flow rate: 80 mL / min, column temperature: 30 ° C.). A fraction solution containing an optically active substance having a retention time of 36 minutes to 45 minutes under the above-mentioned high performance liquid chromatography conditions was washed with a saturated aqueous solution of sodium bicarbonate. The aqueous layer was extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to obtain the optically active form of the title object compound (46 mg) as a colorless amorphous solid.
HPLC-MS: m / z = 467.3 (M + 1); Rt = 1.00 min
実施例４
3-{[(6-{[(5-クロロ-1-メチル-1H-インドール-2-イル)(シクロヘキシル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸 Example 4
3-{[(6-{[(5-Chloro-1-methyl-1H-indol-2-yl) (cyclohexyl) methyl] amino} pyridin-3-yl) carbonyl] (methyl) amino} propanoic acid
Figure JPOXMLDOC01-appb-C000004
Figure JPOXMLDOC01-appb-C000004
（１）5-クロロ-1-メチル-1H-インドール-2-カルボン酸エチル
　5-クロロ-1H-インドール-2-カルボン酸エチル（５．００ｇ）のＮ，Ｎ－ジメチルホルムアミド（５０ｍＬ）溶液に０℃で水素化ナトリウム（６０％、油性、１．０７ｇ）を加え、０℃で１５分撹拌した。反応液にヨウ化メチル（３．８０ｇ）を０℃で加えた後、室温で１時間撹拌した。反応液に氷、および水を加え、析出した固体をろ取し、水で洗浄することで標記目的化合物（４．８２ｇ，９１％）を無色固体として得た。
1H NMR (300 MHz, CDCl3) δ ppm 1.41 (t, J=7.2 Hz, 3 H), 4.06 (s, 3 H), 4.38 (q, J=7.2 Hz, 2 H), 7.22 (s, 1 H), 7.29 - 7.31 (m, 2 H), 7.63 (s, 1 H)． (1) Ethyl 5-chloro-1-methyl-1H-indole-2-carboxylate To a solution of ethyl 5-chloro-1H-indole-2-carboxylate (5.00 g) in N, N-dimethylformamide (50 mL) Sodium hydride (60%, oily, 1.07 g) was added at 0 ° C., and the mixture was stirred at 0 ° C. for 15 minutes. Methyl iodide (3.80 g) was added to the reaction solution at 0 ° C., followed by stirring at room temperature for 1 hour. Ice and water were added to the reaction mixture, and the precipitated solid was collected by filtration and washed with water to give the title object compound (4.82 g, 91%) as a colorless solid.
1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.41 (t, J = 7.2 Hz, 3 H), 4.06 (s, 3 H), 4.38 (q, J = 7.2 Hz, 2 H), 7.22 (s, 1 H), 7.29-7.31 (m, 2 H), 7.63 (s, 1 H).
（２）5-クロロ-1-メチル-1H-インドール-2-カルバルデヒド
　テトラヒドロフラン（２０ｍＬ）に０℃で水素化アルミニウムリチウム（６０８ｍｇ）を加えた。続いて5-クロロ-1-メチル-1H-インドール-2-カルボン酸エチル（３．８１ｇ）のテトラヒドロフラン（１２ｍＬ）溶液を０℃で加えた。混合物を０℃で１時間撹拌した。反応混合物にテトラヒドロフラン（４０ｍＬ）と硫酸ナトリウム十水和物（６．１９ｇ）を０℃で加え、室温で４．５時間撹拌した。不溶物をろ過により除いた後、ろ液を減圧下濃縮し、無色固体（３．２６ｇ）を得た。得られた無色固体（３．２６ｇ）と活性二酸化マンガン（１５．０ｇ）とテトラヒドロフラン（３２ｍＬ）の混合物を５０℃で１．５時間撹拌した。二酸化マンガンをろ過により除去した後、ろ液を減圧下濃縮し、標記目的化合物（２．５９ｇ，８４％）を淡黄色固体として得た。
1H NMR (300 MHz, CDCl3) δ ppm 4.07 (s, 3 H), 7.17 (s, 1 H), 7.29 - 7.40 (m, 2 H), 7.69 (s, 1 H), 9.89 (s, 1 H)． (2) Lithium aluminum hydride (608 mg) was added to 5-chloro-1-methyl-1H-indole-2-carbaldehyde tetrahydrofuran (20 mL) at 0 ° C. Subsequently, a solution of ethyl 5-chloro-1-methyl-1H-indole-2-carboxylate (3.81 g) in tetrahydrofuran (12 mL) was added at 0 ° C. The mixture was stirred at 0 ° C. for 1 hour. Tetrahydrofuran (40 mL) and sodium sulfate decahydrate (6.19 g) were added to the reaction mixture at 0 ° C., and the mixture was stirred at room temperature for 4.5 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give a colorless solid (3.26 g). A mixture of the obtained colorless solid (3.26 g), active manganese dioxide (15.0 g) and tetrahydrofuran (32 mL) was stirred at 50 ° C. for 1.5 hours. After removing manganese dioxide by filtration, the filtrate was concentrated under reduced pressure to obtain the title object compound (2.59 g, 84%) as a pale yellow solid.
1 H NMR (300 MHz, CDCl 3 ) δ ppm 4.07 (s, 3 H), 7.17 (s, 1 H), 7.29-7.40 (m, 2 H), 7.69 (s, 1 H), 9.89 (s, 1 H).
（３）6-{[(5-クロロ-1-メチル-1H-インドール-2-イル)(シクロヘキシル)メチル]アミノ}ピリジン-3-カルボン酸メチル
　5-クロロ-1-メチル-1H-インドール-2-カルバルデヒド（３．３２ｇ）のテトラヒドロフラン（６０ｍＬ）溶液に０℃で１．０Ｍシクロヘキシルマグネシウムブロミドのテトラヒドロフラン溶液（２０ｍＬ）を加え、０℃で３時間撹拌した。反応液に０℃で１．０Ｍシクロヘキシルマグネシウムブロミドのテトラヒドロフラン溶液（２０ｍＬ）をさらに加え、０℃で１０分間撹拌した。１規定塩酸水溶液を加え反応を停止した後、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。ろ過操作後、ろ液を濃縮し、残留物をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル１００：０～５０：５０、v/v）で精製し、褐色固体（２．５４ｇ）を得た。得られた褐色固体（１．０ｇ）と塩化チオニル（３１６μＬ）のテトラヒドロフラン（１０ｍＬ）溶液を室温で２．５時間撹拌した。反応液に氷と飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。ろ過操作後、ろ液を濃縮し、得られた残渣に、6-アミノピリジン-3-カルボン酸メチル（５７５ｍｇ）、ヨウ化ナトリウム（１．０８ｇ）、炭酸ナトリウム（７６３mg）、N,N-ジメチルアセトアミド（１０mL）を加え、80℃で１４時間撹拌した。反応液に水を加え酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。ろ過操作後、ろ液を濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル100：0～90：10、v/v）に付し、標記目的化合物（４７６ｍｇ，１８％）を黄色アモルファス固体として得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 0.88 - 2.02 (m, 11 H), 3.74 (s, 3 H), 3.79 (s, 3 H), 5.24 (br s, 1 H), 6.39 (s, 1 H), 6.59 (d, J=8.7 Hz, 1 H), 7.07 (dd, J=8.7, 2.3 Hz, 1 H), 7.42 (d, J=8.7 Hz, 1 H), 7.51 (d, J=1.9 Hz, 1 H), 7.74 - 7.86 (m, 2 H), 8.54 (d, J=2.3 Hz, 1 H)． (3) 6-{[(5-chloro-1-methyl-1H-indol-2-yl) (cyclohexyl) methyl] amino} pyridine-3-carboxylate methyl 5-chloro-1-methyl-1H-indole- To a solution of 2-carbaldehyde (3.32 g) in tetrahydrofuran (60 mL) was added 1.0 M cyclohexylmagnesium bromide tetrahydrofuran solution (20 mL) at 0 ° C., and the mixture was stirred at 0 ° C. for 3 hr. To the reaction solution was further added 1.0 M cyclohexylmagnesium bromide tetrahydrofuran solution (20 mL) at 0 ° C., and the mixture was stirred at 0 ° C. for 10 minutes. 1N Hydrochloric acid aqueous solution was added to stop the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate 100: 0-50: 50, v / v) to give a brown solid (2.54 g). A solution of the obtained brown solid (1.0 g) and thionyl chloride (316 μL) in tetrahydrofuran (10 mL) was stirred at room temperature for 2.5 hours. Ice and saturated aqueous sodium hydrogen carbonate solution were 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 (575 mg), sodium iodide (1.08 g), sodium carbonate (763 mg), N, N-dimethyl. Acetamide (10 mL) was added and stirred at 80 ° C. for 14 hours. Water 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 the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100: 0 to 90:10, v / v) to give the title object compound (476 mg, 18%) as a yellow amorphous solid.
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 0.88-2.02 (m, 11 H), 3.74 (s, 3 H), 3.79 (s, 3 H), 5.24 (br s, 1 H), 6.39 (s, 1 H), 6.59 (d, J = 8.7 Hz, 1 H), 7.07 (dd, J = 8.7, 2.3 Hz, 1 H), 7.42 (d, J = 8.7 Hz, 1 H), 7.51 ( d, J = 1.9 Hz, 1 H), 7.74-7.86 (m, 2 H), 8.54 (d, J = 2.3 Hz, 1 H).
（４）6-{[(5-クロロ-1-メチル-1H-インドール-2-イル)(シクロヘキシル)メチル]アミノ}ピリジン-3-カルボン酸
　6-{[(5-クロロ-1-メチル-1H-インドール-2-イル)(シクロヘキシル)メチル]アミノ}ピリジン-3-カルボン酸メチル（４５０ｍｇ）および１規定水酸化ナトリウム水溶液（２．１８ｍＬ）のテトラヒドロフラン（２．０ｍＬ）-メタノール（２．０ｍＬ）混合溶液を８０℃で２時間撹拌した。反応混合物を減圧下濃縮した後、水（４ｍＬ）を加え、1規定塩酸水溶液（２．１８ｍＬ）で中和した。生成した沈殿物をろ取し、標記目的化合物（３９９ｍｇ，９２％）を無色アモルファス固体として得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 0.94 - 2.06 (m, 11 H), 3.79 (s, 3 H), 5.09 - 5.31 (m, 1 H), 6.39 (s, 1 H), 6.59 (d, J=8.7 Hz, 1 H), 7.02 - 7.12 (m, 1 H), 7.42 (d, J=8.7 Hz, 1 H), 7.49 - 7.54 (m, 1 H), 7.71 - 7.83 (m, 2 H), 8.52 (d, J=2.3 Hz, 1 H), 12.33 (br s, 1 H)． (4) 6-{[(5-chloro-1-methyl-1H-indol-2-yl) (cyclohexyl) methyl] amino} pyridine-3-carboxylic acid 6-{[(5-chloro-1-methyl- 1H-Indol-2-yl) (cyclohexyl) methyl] amino} methyl pyridine-3-carboxylate (450 mg) and 1N aqueous sodium hydroxide solution (2.18 mL) in tetrahydrofuran (2.0 mL) -methanol (2.0 mL) ) The mixed solution was stirred at 80 ° C. for 2 hours. 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.
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 0.94-2.06 (m, 11 H), 3.79 (s, 3 H), 5.09-5.31 (m, 1 H), 6.39 (s, 1 H), 6.59 (d, J = 8.7 Hz, 1 H), 7.02-7.12 (m, 1 H), 7.42 (d, J = 8.7 Hz, 1 H), 7.49-7.54 (m, 1 H), 7.71-7.83 ( m, 2 H), 8.52 (d, J = 2.3 Hz, 1 H), 12.33 (br s, 1 H).
（５）3-{[(6-{[(5-クロロ-1-メチル-1H-インドール-2-イル)(シクロヘキシル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸エチル
　6-{[(5-クロロ-1-メチル-1H-インドール-2-イル)(シクロヘキシル)メチル]アミノ}ピリジン-3-カルボン酸（３９０ｍｇ）、３－（メチルアミノ）プロパン酸エチル（１８１ｍｇ）、1-ヒドロキシベンゾトリアゾール・１水和物（２０８ｍｇ）、トリエチルアミン（３７８μＬ）、1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド 塩酸塩（２６１ｍｇ）およびN,N-ジメチルホルムアミド（５ｍＬ）の混合物を室温で１６時間撹拌した。飽和塩化アンモニウム水溶液を加え反応を停止した後、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、ろ過操作後、ろ液を減圧下濃縮した。残留物をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル１００：０～５０：５０、v/v）で精製し、標記目的化合物（３３９ｍｇ，６８％）を黄色アモルファス固体として得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 0.98 - 1.23 (m, 8 H), 1.42 - 1.97 (m, 6 H), 2.58 (t, J=7.2 Hz, 2 H), 2.91 (s, 3 H), 3.57 (t, J=7.2 Hz, 2 H), 3.79 (s, 3 H), 3.98 - 4.06 (m, 2 H), 5.19 (t, J=8.5 Hz, 1 H), 6.38 (s, 1 H), 6.55 (d, J=8.7 Hz, 1 H), 7.06 (dd, J=8.7, 2.3 Hz, 1 H), 7.28 - 7.44 (m, 3 H), 7.50 (d, J=1.9 Hz, 1 H), 8.03 (d, J=2.3 Hz, 1 H)． (5) 3-{[(6-{[(5-Chloro-1-methyl-1H-indol-2-yl) (cyclohexyl) methyl] amino} pyridin-3-yl) carbonyl] (methyl) amino} propane Ethyl 6-{[(5-chloro-1-methyl-1H-indol-2-yl) (cyclohexyl) methyl] amino} pyridine-3-carboxylic acid (390 mg), ethyl 3- (methylamino) propanoate ( 181 mg), 1-hydroxybenzotriazole monohydrate (208 mg), triethylamine (378 μL), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (261 mg) and N, N-dimethylformamide (5 mL) ) Was stirred at room temperature for 16 hours. Saturated aqueous ammonium chloride solution was added to stop the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate 100: 0-50: 50, v / v) to give the title object compound (339 mg, 68%) as a yellow amorphous solid.
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 0.98-1.23 (m, 8 H), 1.42-1.97 (m, 6 H), 2.58 (t, J = 7.2 Hz, 2 H), 2.91 (s , 3 H), 3.57 (t, J = 7.2 Hz, 2 H), 3.79 (s, 3 H), 3.98-4.06 (m, 2 H), 5.19 (t, J = 8.5 Hz, 1 H), 6.38 (s, 1 H), 6.55 (d, J = 8.7 Hz, 1 H), 7.06 (dd, J = 8.7, 2.3 Hz, 1 H), 7.28-7.44 (m, 3 H), 7.50 (d, J = 1.9 Hz, 1 H), 8.03 (d, J = 2.3 Hz, 1 H).
（６）3-{[(6-{[(5-クロロ-1-メチル-1H-インドール-2-イル)(シクロヘキシル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸
　3-{[(6-{[(5-クロロ-1-メチル-1H-インドール-2-イル)(シクロヘキシル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸エチル（３１０ｍｇ）と1規定水酸化ナトリウム水溶液（１．２２ｍＬ）のエタノール（２．０ｍＬ）-テトラヒドロフラン（２．０ｍＬ）混合溶液を室温で１時間撹拌した。溶媒を減圧留去した後に、水（４．０ｍＬ）を加え、１規定塩酸水溶液（１．２２ｍＬ）で中和した。生成した沈殿物をろ取することで標記目的化合物（２３１ｍｇ，７９％）を無色アモルファス固体として得た。
1H NMR (300 MHz, CDCl3) δ ppm 0.91 - 2.15 (m, 11 H), 2.64 (br s, 2 H), 3.06 (s, 3 H), 3.67 - 3.79 (m, 5 H), 4.48 (br s, 1 H), 6.35 - 6.46 (m, 2 H), 7.07 - 7.14 (m, 1 H), 7.16 - 7.22 (m, 1 H), 7.44 - 7.55 (m, 2 H), 8.05 (br s, 1 H)．
HPLC-MS:m/z=483.4(M+1); Rt=1.06 min (6) 3-{[(6-{[(5-Chloro-1-methyl-1H-indol-2-yl) (cyclohexyl) methyl] amino} pyridin-3-yl) carbonyl] (methyl) amino} propane Acid 3-{[(6-{[(5-Chloro-1-methyl-1H-indol-2-yl) (cyclohexyl) methyl] amino} pyridin-3-yl) carbonyl] (methyl) amino} propanoate (310 mg) and a 1N aqueous sodium hydroxide solution (1.22 mL) in ethanol (2.0 mL) -tetrahydrofuran (2.0 mL) were mixed at room temperature for 1 hour. After the solvent was distilled off under reduced pressure, water (4.0 mL) was added and neutralized with a 1N aqueous hydrochloric acid solution (1.22 mL). The resulting precipitate was collected by filtration to give the title object compound (231 mg, 79%) as a colorless amorphous solid.
1 H NMR (300 MHz, CDCl 3 ) δ ppm 0.91-2.15 (m, 11 H), 2.64 (br s, 2 H), 3.06 (s, 3 H), 3.67-3.79 (m, 5 H), 4.48 (br s, 1 H), 6.35-6.46 (m, 2 H), 7.07-7.14 (m, 1 H), 7.16-7.22 (m, 1 H), 7.44-7.55 (m, 2 H), 8.05 ( br s, 1 H).
HPLC-MS: m / z = 483.4 (M + 1); Rt = 1.06 min
実施例５
3-{[(6-{[(5-クロロ-1-メチル-1H-インドール-2-イル)(シクロヘキシル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸 Example 5
3-{[(6-{[(5-Chloro-1-methyl-1H-indol-2-yl) (cyclohexyl) methyl] amino} pyridin-3-yl) carbonyl] (methyl) amino} propanoic acid
Figure JPOXMLDOC01-appb-C000005
Figure JPOXMLDOC01-appb-C000005
　実施例４の（６）で合成した3-{[(6-{[(5-クロロ-1-メチル-1H-インドール-2-イル)(シクロヘキシル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸（１５６ｍｇ）を高速液体クロマトグラフィー（カラム：ＣＨＩＲＡＬＰＡＫ ＡＤ（５０ｍｍＩＤ×５００ｍｍＬ、ダイセル化学工業製）、移動相：ヘキサン／２－プロパノール／ギ酸（５００／５００／１、ｖ／ｖ／ｖ）、流速：６０ｍＬ／ｍｉｎ、カラム温度：３０℃）を用いて分画した。上記の高速液体クロマトグラフィー条件にて保持時間が１９分から２４分の光学活性体を含有する分画液を飽和炭酸水素ナトリウム水溶液で洗浄した。水層を酢酸エチルで抽出し、有機層を合わせて飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。ろ過操作後、ろ液を濃縮した。得られた残渣に酢酸エチルを加え、水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。ろ過操作後、ろ液を濃縮し、標記目的化合物の光学活性体（６１ｍｇ）を無色アモルファス固体として得た。
HPLC-MS:m/z=483.4(M+1); Rt=1.07 min 3-{[(6-{[(5-Chloro-1-methyl-1H-indol-2-yl) (cyclohexyl) methyl] amino} pyridin-3-yl) carbonyl synthesized in Example 4 (6) ] (Methyl) amino} propanoic acid (156 mg) was subjected to high performance liquid chromatography (column: CHIRALPAK AD (50 mm ID × 500 mm L, manufactured by Daicel Chemical Industries), mobile phase: hexane / 2-propanol / formic acid (500/500/1, v / V / v), flow rate: 60 mL / min, column temperature: 30 ° C.). A fraction solution containing an optically active substance with a retention time of 19 to 24 minutes under the above-mentioned high performance liquid chromatography conditions was washed with a saturated aqueous solution of sodium bicarbonate. The aqueous layer was extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. Ethyl acetate was added to the resulting residue, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to obtain the optically active form of the title target compound (61 mg) as a colorless amorphous solid.
HPLC-MS: m / z = 483.4 (M + 1); Rt = 1.07 min
実施例６
3-{[(6-{[(5-クロロ-1-メチル-1H-インドール-2-イル)(シクロヘキシル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸 Example 6
3-{[(6-{[(5-Chloro-1-methyl-1H-indol-2-yl) (cyclohexyl) methyl] amino} pyridin-3-yl) carbonyl] (methyl) amino} propanoic acid
Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-C000006
　実施例４の（６）で合成した3-{[(6-{[(5-クロロ-1-メチル-1H-インドール-2-イル)(シクロヘキシル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸（１５６ｍｇ）を高速液体クロマトグラフィー（カラム：ＣＨＩＲＡＬＰＡＫ ＡＤ（５０ｍｍＩＤ×５００ｍｍＬ、ダイセル化学工業製）、移動相：ヘキサン／２－プロパノール／ギ酸（５００／５００／１、ｖ／ｖ／ｖ）、流速：６０ｍＬ／ｍｉｎ、カラム温度：３０℃）を用いて分画した。上記の高速液体クロマトグラフィー条件にて保持時間が３２分から４１分の光学活性体を含有する分画液を飽和炭酸水素ナトリウム水溶液で洗浄した。水層を酢酸エチルで抽出し、有機層を合わせて飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。ろ過操作後、ろ液を濃縮した。得られた残渣に酢酸エチルを加え、水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。ろ過操作後、ろ液を濃縮し、標記目的化合物の光学活性体（６９ｍｇ）を無色アモルファス固体として得た。
HPLC-MS:m/z=483.4(M+1); Rt=1.07 min 3-{[(6-{[(5-Chloro-1-methyl-1H-indol-2-yl) (cyclohexyl) methyl] amino} pyridin-3-yl) carbonyl synthesized in Example 4 (6) ] (Methyl) amino} propanoic acid (156 mg) was subjected to high performance liquid chromatography (column: CHIRALPAK AD (50 mm ID × 500 mm L, manufactured by Daicel Chemical Industries), mobile phase: hexane / 2-propanol / formic acid (500/500/1, v / V / v), flow rate: 60 mL / min, column temperature: 30 ° C.). A fraction solution containing an optically active substance having a retention time of 32 minutes to 41 minutes under the above-mentioned high performance liquid chromatography conditions was washed with a saturated aqueous solution of sodium bicarbonate. The aqueous layer was extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. Ethyl acetate was added to the resulting residue, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to obtain the optically active substance (69 mg) of the title object compound as a colorless amorphous solid.
HPLC-MS: m / z = 483.4 (M + 1); Rt = 1.07 min
実施例７
3-{[(6-{[(5-クロロ-1-メチル-1H-インドール-2-イル)(シクロペンチル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸 Example 7
3-{[(6-{[(5-Chloro-1-methyl-1H-indol-2-yl) (cyclopentyl) methyl] amino} pyridin-3-yl) carbonyl] (methyl) amino} propanoic acid
Figure JPOXMLDOC01-appb-C000007
Figure JPOXMLDOC01-appb-C000007
（１）6-{[(5-クロロ-1-メチル-1H-インドール-2-イル)(シクロペンチル)メチル]アミノ}ピリジン-3-カルボン酸メチル
　実施例４の（２）で合成した5-クロロ-1-メチル-1H-インドール-2-カルバルデヒド（１５．０ｇ）のテトラヒドロフラン（２００ｍＬ）溶液に窒素雰囲気下、０℃で１．０Ｍシクロペンチルマグネシウムブロミドのテトラヒドロフラン溶液（７８．０ｍＬ）を２０分かけて加えた後に、０℃で２０分間撹拌した。反応液に氷と水を加え反応を停止した後、酢酸エチルで抽出した。抽出液を１規定塩酸水溶液、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。ろ過操作後、ろ液を濃縮し、残留物をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル１００：０～８０：２０、v/v）で精製し、赤色固体（２．１０ｇ）を得た。得られた赤色固体（２．１０ｇ）と塩化チオニル（７００μＬ）のテトラヒドロフラン（２０ｍＬ）溶液を室温で２時間撹拌した。反応液に０℃に冷却した飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。ろ過操作後、ろ液を濃縮し、得られた残渣に、6-アミノピリジン-3-カルボン酸メチル（２．３３ｇ）、ヨウ化ナトリウム（２．３９ｇ）、炭酸ナトリウム（１．６９ｇ）、N,N-ジメチルアセトアミド（２０mL）を加え、80℃で１２時間撹拌した。反応液に水を加え酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。ろ過操作後、ろ液を濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル１００：０～９０：１０、v/v）に付し、標記目的化合物（１．０４ｇ， ３％）をオレンジ色アモルファス固体として得た。
1H NMR (300 MHz, CDCl3) δ ppm 1.21 - 1.90 (m, 8 H), 2.45 - 2.64 (m, 1 H), 3.72 (s, 3 H), 3.85 (s, 3 H), 4.99 (d, J=8.7 Hz, 1 H), 5.33 (t, J=9.0 Hz, 1 H), 6.28 (d, J=8.3 Hz, 1 H), 6.38 (s, 1 H), 7.07 - 7.20 (m, 2 H), 7.46 - 7.53 (m, 1 H), 7.90 (dd, J=8.7, 2.3 Hz, 1 H), 8.75 (d, J=1.9 Hz, 1 H)． (1) methyl 6-{[(5-chloro-1-methyl-1H-indol-2-yl) (cyclopentyl) methyl] amino} pyridine-3-carboxylate 5-synthesized in (2) of Example 4 To a solution of chloro-1-methyl-1H-indole-2-carbaldehyde (15.0 g) in tetrahydrofuran (200 mL) was added 1.0 M cyclopentylmagnesium bromide tetrahydrofuran solution (78.0 mL) at 0 ° C. for 20 minutes under a nitrogen atmosphere. After adding, the mixture was stirred at 0 ° C. for 20 minutes. Ice and water were added to the reaction solution to stop the reaction, followed by extraction with ethyl acetate. The extract was washed with 1N aqueous hydrochloric acid solution and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate 100: 0-80: 20, v / v) to obtain a red solid (2.10 g). A solution of the obtained red solid (2.10 g) and thionyl chloride (700 μL) in tetrahydrofuran (20 mL) was stirred at room temperature for 2 hours. 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. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100: 0 to 90:10, v / v) to give the title object compound (1.04 g, 3%) as an orange amorphous solid.
1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.21-1.90 (m, 8 H), 2.45-2.64 (m, 1 H), 3.72 (s, 3 H), 3.85 (s, 3 H), 4.99 ( d, J = 8.7 Hz, 1 H), 5.33 (t, J = 9.0 Hz, 1 H), 6.28 (d, J = 8.3 Hz, 1 H), 6.38 (s, 1 H), 7.07-7.20 (m , 2 H), 7.46-7.53 (m, 1 H), 7.90 (dd, J = 8.7, 2.3 Hz, 1 H), 8.75 (d, J = 1.9 Hz, 1 H).
（２）6-{[(5-クロロ-1-メチル-1H-インドール-2-イル)(シクロペンチル)メチル]アミノ}ピリジン-3-カルボン酸
　6-{[(5-クロロ-1-メチル-1H-インドール-2-イル)(シクロペンチル)メチル]アミノ}ピリジン-3-カルボン酸メチル（１．０４ｇ）および１規定水酸化ナトリウム水溶液（５．２２ｍＬ）のテトラヒドロフラン（６．０ｍＬ）-メタノール（６．０ｍＬ）混合溶液を８０℃で２時間撹拌した。反応混合物を減圧下濃縮した後、水（１０ｍＬ）を加え、1規定塩酸水溶液（５．２２ｍＬ）で中和した。生成した沈殿物をろ取し、標記目的化合物（９１２ｍｇ，９１％）を淡褐色固体として得た。
1H NMR (300 MHz, CDCl3) δ ppm 1.30 - 2.74 (m, 9 H), 3.77 (s, 3 H), 4.79 (br s, 1H), 6.41 - 6.44 (m, 2 H), 7.06 - 7.23 (m, 3 H), 7.48 - 7.51 (m, 1 H), 7.98 - 8.11 (m, 1 H), 8.73 (d, J=1.9 Hz, 1 H)． (2) 6-{[(5-chloro-1-methyl-1H-indol-2-yl) (cyclopentyl) methyl] amino} pyridine-3-carboxylic acid 6-{[(5-chloro-1-methyl- 1H-Indol-2-yl) (cyclopentyl) methyl] amino} pyridine-3-carboxylate (1.04 g) and 1N aqueous sodium hydroxide (5.22 mL) in tetrahydrofuran (6.0 mL) -methanol (6 0.0 mL) The mixed solution was stirred at 80 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, water (10 mL) was added, and the mixture was neutralized with 1N aqueous hydrochloric acid solution (5.22 mL). The resulting precipitate was collected by filtration to give the title object compound (912 mg, 91%) as a pale brown solid.
1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.30-2.74 (m, 9 H), 3.77 (s, 3 H), 4.79 (br s, 1H), 6.41-6.44 (m, 2 H), 7.06- 7.23 (m, 3 H), 7.48-7.51 (m, 1 H), 7.98-8.11 (m, 1 H), 8.73 (d, J = 1.9 Hz, 1 H).
（３）3-{[(6-{[(5-クロロ-1-メチル-1H-インドール-2-イル)(シクロペンチル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸エチル
　6-{[(5-クロロ-1-メチル-1H-インドール-2-イル)(シクロペンチル)メチル]アミノ}ピリジン-3-カルボン酸（８９４ｍｇ）、3－（メチルアミノ）プロパン酸エチル（３７２ｍｇ）、1-ヒドロキシベンゾトリアゾール・１水和物（４２７ｍｇ）、トリエチルアミン（３８９μＬ）、1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド 塩酸塩（５３５ｍｇ）およびN,N-ジメチルホルムアミド（９ｍＬ）の混合物を室温で１２時間撹拌した。水を加え反応を停止した後、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、ろ過操作後、ろ液を減圧下濃縮した。残留物をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル１００：０～５０：５０、v/v）で精製し、標記目的化合物（４８０ｍｇ，４１％）を無色アモルファス固体として得た。
1H NMR (300 MHz, CDCl3) δ ppm 1.20 - 1.30 (m, 3 H), 1.53 - 2.76 (m, 11 H), 3.07 (s, 3 H), 3.60 - 3.82 (m, 5 H), 4.07 - 4.21 (m, 2 H), 4.80 (d, J=8.7 Hz, 1 H), 5.24 (t, J=9.1 Hz, 1 H), 6.29 (d, J=8.7 Hz, 1 H), 6.38 (s, 1 H), 7.08 - 7.22 (m, 2 H), 7.46 (dd, J=8.7, 2.3 Hz, 1 H), 7.50 (d, J=1.5 Hz, 1 H), 8.22 (d, J=2.3 Hz, 1 H)． (3) 3-{[(6-{[(5-Chloro-1-methyl-1H-indol-2-yl) (cyclopentyl) methyl] amino} pyridin-3-yl) carbonyl] (methyl) amino} propane Ethyl 6-{[(5-chloro-1-methyl-1H-indol-2-yl) (cyclopentyl) methyl] amino} pyridine-3-carboxylic acid (894 mg), ethyl 3- (methylamino) propanoate ( 372 mg), 1-hydroxybenzotriazole monohydrate (427 mg), triethylamine (389 μL), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (535 mg) and N, N-dimethylformamide (9 mL) ) Was stirred at room temperature for 12 hours. Water was added to stop the reaction, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate 100: 0-50: 50, v / v) to give the title object compound (480 mg, 41%) as a colorless amorphous solid.
1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.20-1.30 (m, 3 H), 1.53-2.76 (m, 11 H), 3.07 (s, 3 H), 3.60-3.82 (m, 5 H), 4.07-4.21 (m, 2 H), 4.80 (d, J = 8.7 Hz, 1 H), 5.24 (t, J = 9.1 Hz, 1 H), 6.29 (d, J = 8.7 Hz, 1 H), 6.38 (s, 1 H), 7.08-7.22 (m, 2 H), 7.46 (dd, J = 8.7, 2.3 Hz, 1 H), 7.50 (d, J = 1.5 Hz, 1 H), 8.22 (d, J = 2.3 Hz, 1 H).
（４）3-{[(6-{[(5-クロロ-1-メチル-1H-インドール-2-イル)(シクロペンチル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸
　3-{[(6-{[(5-クロロ-1-メチル-1H-インドール-2-イル)(シクロペンチル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸エチル（２１０ｍｇ）と1規定水酸化ナトリウム水溶液（４２０μＬ）のエタノール（１．０ｍＬ）-テトラヒドロフラン（１．０ｍＬ）混合溶液を室温で１時間撹拌した。1規定水酸化ナトリウム水溶液（４２０μＬ）をさらに加え室温で１５分撹拌した。溶媒を減圧留去した後に、水（２．０ｍＬ）を加え、１規定塩酸水溶液（８４０μＬ）で中和した。生成した沈殿物をろ取することで標記目的化合物（１７４ｍｇ，８８％）を無色アモルファス固体として得た。
1H NMR (300 MHz, CDCl3) δ ppm 1.00 - 2.73 (m, 11 H), 3.05 (s, 3 H), 3.69 - 3.86 (m, 5 H), 4.53 (br s, 1 H), 6.41 (s, 1 H), 6.47 (d, J=8.7 Hz, 1 H), 7.05 - 7.21 (m, 2 H), 7.46 - 7.55 (m, 2 H), 8.05 (br s, 1 H)．
HPLC-MS:m/z=469.3(M+1); Rt=1.02 min (4) 3-{[(6-{[(5-Chloro-1-methyl-1H-indol-2-yl) (cyclopentyl) methyl] amino} pyridin-3-yl) carbonyl] (methyl) amino} propane Acid 3-{[(6-{[(5-Chloro-1-methyl-1H-indol-2-yl) (cyclopentyl) methyl] amino} pyridin-3-yl) carbonyl] (methyl) amino} propanoate (210 mg) and a 1N aqueous sodium hydroxide solution (420 μL) in ethanol (1.0 mL) -tetrahydrofuran (1.0 mL) were mixed at room temperature for 1 hour. 1N Aqueous sodium hydroxide solution (420 μL) was further added, and the mixture was stirred at room temperature for 15 min. After the solvent was distilled off under reduced pressure, water (2.0 mL) was added, and the mixture was neutralized with 1N hydrochloric acid aqueous solution (840 μL). The resulting precipitate was collected by filtration to give the title object compound (174 mg, 88%) as a colorless amorphous solid.
1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.00-2.73 (m, 11 H), 3.05 (s, 3 H), 3.69-3.86 (m, 5 H), 4.53 (br s, 1 H), 6.41 (s, 1 H), 6.47 (d, J = 8.7 Hz, 1 H), 7.05-7.21 (m, 2 H), 7.46-7.55 (m, 2 H), 8.05 (br s, 1 H).
HPLC-MS: m / z = 469.3 (M + 1); Rt = 1.02 min
実施例８
3-{[(6-{[(5-クロロ-1-メチル-1H-インドール-2-イル)(シクロペンチル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸 Example 8
3-{[(6-{[(5-Chloro-1-methyl-1H-indol-2-yl) (cyclopentyl) methyl] amino} pyridin-3-yl) carbonyl] (methyl) amino} propanoic acid
Figure JPOXMLDOC01-appb-C000008
Figure JPOXMLDOC01-appb-C000008
　実施例７の（４）で合成した3-{[(6-{[(5-クロロ-1-メチル-1H-インドール-2-イル)(シクロペンチル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸（１４２ｍｇ）を高速液体クロマトグラフィー（カラム：ＣＨＩＲＡＬＰＡＫ ＡＤ（５０ｍｍＩＤ×５００ｍｍＬ、ダイセル化学工業製）、移動相：ヘキサン／２－プロパノール／ギ酸（７００／３００／１、ｖ／ｖ／ｖ）、流速：８０ｍＬ／ｍｉｎ、カラム温度：３０℃）を用いて分画した。上記の高速液体クロマトグラフィー条件にて保持時間が２６分から３４分の光学活性体を含有する分画液を飽和炭酸水素ナトリウム水溶液で洗浄した。水層を酢酸エチルで抽出し、有機層を合わせて飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。ろ過操作後、ろ液を濃縮した。得られた残渣に酢酸エチルを加え、水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。ろ過操作後、ろ液を濃縮し、標記目的化合物の光学活性体（４５ｍｇ）を無色アモルファス固体として得た。
HPLC-MS:m/z=469.4(M+1); Rt=1.03 min 3-{[(6-{[(5-Chloro-1-methyl-1H-indol-2-yl) (cyclopentyl) methyl] amino} pyridin-3-yl) carbonyl synthesized in Example 7 (4) ] (Methyl) amino} propanoic acid (142 mg) was subjected to high performance liquid chromatography (column: CHIRALPAK AD (50 mm ID × 500 mm L, manufactured by Daicel Chemical Industries), mobile phase: hexane / 2-propanol / formic acid (700/300/1, v / V / v), flow rate: 80 mL / min, column temperature: 30 ° C.). A fraction containing the optically active substance with a retention time of 26 to 34 minutes under the above-mentioned high performance liquid chromatography conditions was washed with a saturated aqueous solution of sodium bicarbonate. The aqueous layer was extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. Ethyl acetate was added to the resulting residue, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to obtain the optically active form of the title target compound (45 mg) as a colorless amorphous solid.
HPLC-MS: m / z = 469.4 (M + 1); Rt = 1.03 min
実施例９
3-{[(6-{[(5-クロロ-1-メチル-1H-インドール-2-イル)(シクロペンチル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸 Example 9
3-{[(6-{[(5-Chloro-1-methyl-1H-indol-2-yl) (cyclopentyl) methyl] amino} pyridin-3-yl) carbonyl] (methyl) amino} propanoic acid
Figure JPOXMLDOC01-appb-C000009
Figure JPOXMLDOC01-appb-C000009
　実施例７の（４）で合成した3-{[(6-{[(5-クロロ-1-メチル-1H-インドール-2-イル)(シクロペンチル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸（１４２ｍｇ）を高速液体クロマトグラフィー（カラム：ＣＨＩＲＡＬＰＡＫ ＡＤ（５０ｍｍＩＤ×５００ｍｍＬ、ダイセル化学工業製）、移動相：ヘキサン／２－プロパノール／ギ酸（７００／３００／１、ｖ／ｖ／ｖ）、流速：８０ｍＬ／ｍｉｎ、カラム温度：３０℃）を用いて分画した。上記の高速液体クロマトグラフィー条件にて保持時間が４２分から５４分の光学活性体を含有する分画液を飽和炭酸水素ナトリウム水溶液で洗浄した。水層を酢酸エチルで抽出し、有機層を合わせて飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。ろ過操作後、ろ液を濃縮した。得られた残渣に酢酸エチルを加え、水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。ろ過操作後、ろ液を濃縮し、標記目的化合物の光学活性体（３１ｍｇ）を無色アモルファス固体として得た。
HPLC-MS:m/z=469.4(M+1); Rt=1.03 min 3-{[(6-{[(5-Chloro-1-methyl-1H-indol-2-yl) (cyclopentyl) methyl] amino} pyridin-3-yl) carbonyl synthesized in Example 7 (4) ] (Methyl) amino} propanoic acid (142 mg) was subjected to high performance liquid chromatography (column: CHIRALPAK AD (50 mm ID × 500 mm L, manufactured by Daicel Chemical Industries), mobile phase: hexane / 2-propanol / formic acid (700/300/1, v / V / v), flow rate: 80 mL / min, column temperature: 30 ° C.). A fraction solution containing an optically active substance having a retention time of 42 to 54 minutes under the above-mentioned high performance liquid chromatography conditions was washed with a saturated aqueous solution of sodium bicarbonate. The aqueous layer was extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. Ethyl acetate was added to the resulting residue, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to obtain the optically active form of the title target compound (31 mg) as a colorless amorphous solid.
HPLC-MS: m / z = 469.4 (M + 1); Rt = 1.03 min
実施例10
3-{[(4-{[(5-クロロ-3-メチルチエノ[2,3-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}フェニル)カルボニル](メチル)アミノ}プロパン酸 Example 10
3-{[(4-{[(5-Chloro-3-methylthieno [2,3-c] pyridin-2-yl) (cyclohexyl) methyl] amino} phenyl) carbonyl] (methyl) amino} propanoic acid
Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000010
（１）1-(2,5-ジクロロピリジン-4-イル)エタノン
　2,5-ジクロロイソニコチン酸（5.0 g）のテトラヒドロフラン（40 mL）溶液に塩化オキサリル（2.68 mL）とN,N-ジメチルホルムアミド（1滴）を加えた後、室温で2時間攪拌した。混合物を減圧下濃縮して白色固体を得た。得られた固体のN,N-ジメチルアセトアミド（40 mL）溶液にN,O-ジメチルヒドロキシルアミン塩酸塩（3.8 g）を加えた後、室温で終夜攪拌した。水を加えて反応を停止した後、酢酸エチルで抽出した。抽出液を飽和塩化アンモニウム水溶液および飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し、減圧下濃縮して白色固体（6.23 g）を得た。得られた固体（6.23 g）のテトラヒドロフラン（50 mL）溶液に0℃でメチルマグネシウムブロミドの3.0 Mテトラヒドロフラン溶液（26 mL）を加えた後、30分間攪拌した。飽和塩化アンモニウム水溶液を加えて反応を停止した後、酢酸エチルで抽出した。抽出液を水および飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）で精製し、標記目的化合物（4.67 g, 95%）を無色油状物として得た。
1H NMR (300 MHz, CDCl3) δ ppm 2.65 (s, 3H), 7.40 (s, 1H), 8.46 (s, 1H). (1) 1- (2,5-dichloropyridin-4-yl) ethanone To a solution of 2,5-dichloroisonicotinic acid (5.0 g) in tetrahydrofuran (40 mL) was added oxalyl chloride (2.68 mL) and N, N-dimethyl. After formamide (1 drop) was added, the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to give a white solid. N, O-dimethylhydroxylamine hydrochloride (3.8 g) was added to a solution of the obtained solid N, N-dimethylacetamide (40 mL), and the mixture was stirred at room temperature overnight. The reaction was stopped by adding water, followed by extraction with ethyl acetate. The extract was washed with saturated aqueous ammonium chloride solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a white solid (6.23 g). To a solution of the obtained solid (6.23 g) in tetrahydrofuran (50 mL) was added a 3.0 M solution of methylmagnesium bromide in tetrahydrofuran (26 mL) at 0 ° C., and the mixture was stirred for 30 min. Saturated aqueous ammonium chloride solution was added to stop the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with water and 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 (4.67 g, 95%) as a colorless oil.
1 H NMR (300 MHz, CDCl 3 ) δ ppm 2.65 (s, 3H), 7.40 (s, 1H), 8.46 (s, 1H).
（２）5-クロロ-3-メチルチエノ[2,3-c]ピリジン-2-カルボン酸エチル
　1-(2,5-ジクロロピリジン-4-イル)エタノン（4.67 g）、チオグリコール酸エチル（2.97 mL）およびN,N-ジメチルホルムアミド（50 mL）の混合物に炭酸カリウム（10.2 g）を加え、50℃で3日間攪拌した。混合物を水にあけて反応を停止した後、酢酸エチルで抽出した。抽出液を水および飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し、減圧下濃縮して標記目的化合物 （5.73 g, 91%）を白色粉末として得た。
1H NMR (300 MHz, CDCl3) δ ppm 1.43 (t, J=7.0 Hz, 3H), 2.73 (s, 3H), 4.43 (q, J=7.2 Hz, 2H), 7.73 (d, J=1.1 Hz, 1H), 8.91 (d, J=1.1 Hz, 1H). (2) Ethyl 5-chloro-3-methylthieno [2,3-c] pyridine-2-carboxylate 1- (2,5-dichloropyridin-4-yl) ethanone (4.67 g), ethyl thioglycolate (2.97 mL) and N, N-dimethylformamide (50 mL) were added potassium carbonate (10.2 g), and the mixture was stirred at 50 ° C. for 3 days. The mixture was poured into water to stop the reaction, and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title object compound (5.73 g, 91%) as a white powder.
1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.43 (t, J = 7.0 Hz, 3H), 2.73 (s, 3H), 4.43 (q, J = 7.2 Hz, 2H), 7.73 (d, J = 1.1 Hz, 1H), 8.91 (d, J = 1.1 Hz, 1H).
（３）(5-クロロ-3-メチルチエノ[2,3-c]ピリジン-2-イル)メタノール
　5-クロロ-3-メチルチエノ[2,3-c]ピリジン-2-カルボン酸エチル（5.73 g）と塩化カルシウム（5.46 g）、テトラヒドロフラン（50 mL）およびエタノール（50 mL）の混合物に0℃で水素化ホウ素ナトリウム（3.72 g）を加えた後、室温で終夜攪拌した。飽和塩化アンモニウム水溶液を加えて反応を停止した後、減圧下濃縮してテトラヒドロフランとエタノールを除き、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し、減圧下濃縮して標記目的化合物（4.28 g, 81%）を白色固体として得た。
1H NMR (300 MHz, CDCl3) δ ppm 2.06 (t, J=5.7 Hz, 1H), 2.35 (s, 3H), 4.98 (d, J=5.3 Hz, 2H), 7.56 (d, J=0.8 Hz, 1H), 8.82 (d, J=0.8 Hz, 1H). (3) (5-chloro-3-methylthieno [2,3-c] pyridin-2-yl) methanol 5-chloro-3-methylthieno [2,3-c] pyridine-2-carboxylate (5.73 g) To a mixture of calcium chloride (5.46 g), tetrahydrofuran (50 mL) and ethanol (50 mL) was added sodium borohydride (3.72 g) at 0 ° C., and the mixture was stirred at room temperature overnight. Saturated aqueous ammonium chloride solution was added to stop the reaction, and the mixture was concentrated under reduced pressure to remove tetrahydrofuran and ethanol, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title object compound (4.28 g, 81%) as a white solid.
1 H NMR (300 MHz, CDCl 3 ) δ ppm 2.06 (t, J = 5.7 Hz, 1H), 2.35 (s, 3H), 4.98 (d, J = 5.3 Hz, 2H), 7.56 (d, J = 0.8 Hz, 1H), 8.82 (d, J = 0.8 Hz, 1H).
（４）(5-クロロ-3-メチルチエノ[2,3-c]ピリジン-2-イル)(シクロヘキシル)メタノール
　(5-クロロ-3-メチルチエノ[2,3-c]ピリジン-2-イル)メタノール（580 mg）、二酸化マンガン（2.5 g）およびテトラヒドロフラン（10 mL）の混合物を50℃で終夜攪拌した。二酸化マンガンをろ別した後、ろ液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）で精製し、黄色固体（431 mg）を得た。得られた固体（431 mg）のテトラヒドロフラン（20 mL）溶液に0℃でシクロヘキシルマグネシウムブロミドの1.0 Mテトラヒドロフラン溶液（3.1 mL）を加え、1時間攪拌した。飽和塩化アンモニウム水溶液を加えて反応を停止した後、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）で精製し、標記目的化合物（370 mg, 45%）をアモルファス固体として得た。
1H NMR (300 MHz, CDCl3) δ ppm 0.98-1.96 (m, 10H), 2.10 (d, J=12.9 Hz, 1H), 2.34 (s, 3H), 4.87 (dd, J=7.8, 2.1 Hz, 1H), 7.54 (d, J= 0.8 Hz, 1H), 8.80 (d, J=1.1 Hz, 1H). (4) (5-Chloro-3-methylthieno [2,3-c] pyridin-2-yl) (cyclohexyl) methanol (5-Chloro-3-methylthieno [2,3-c] pyridin-2-yl) methanol (580 mg), a mixture of manganese dioxide (2.5 g) and tetrahydrofuran (10 mL) was stirred at 50 ° C. overnight. After manganese dioxide was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give a yellow solid (431 mg). To a solution of the obtained solid (431 mg) in tetrahydrofuran (20 mL) was added 1.0 M tetrahydrofuran solution (3.1 mL) of cyclohexylmagnesium bromide at 0 ° C., and the mixture was stirred for 1 hr. Saturated aqueous ammonium chloride 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 (370 mg, 45%) as an amorphous solid.
1 H NMR (300 MHz, CDCl 3 ) δ ppm 0.98-1.96 (m, 10H), 2.10 (d, J = 12.9 Hz, 1H), 2.34 (s, 3H), 4.87 (dd, J = 7.8, 2.1 Hz , 1H), 7.54 (d, J = 0.8 Hz, 1H), 8.80 (d, J = 1.1 Hz, 1H).
（５）4-{[(5-クロロ-3-メチルチエノ[2,3-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}安息香酸メチル
　(5-クロロ-3-メチルチエノ[2,3-c]ピリジン-2-イル)(シクロヘキシル)メタノール（370 mg）、4-メチルモルホリン N-オキシド（332 mg）およびアセトニトリル（7 mL）の混合物に過ルテニウム酸テトラプロピルアンモニウム（44 mg）を加え、室温で3日間攪拌した後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）で精製し、黄色固体（187 mg）を得た。得られた固体（187 mg）、4-アミノ安息香酸メチル（115 mg）、トリエチルアミン（708 μL）およびジクロロメタン（3 mL）の混合物に塩化チタン（IV）の1.0 Mジクロロメタン溶液（762 μL）を加えた後、室温で終夜攪拌した。飽和炭酸水素ナトリウム水溶液を加えて反応を停止した後、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し、減圧下濃縮して暗赤色油状物を得た。得られた油状物、シアノ水素化ホウ素ナトリウム（80 mg）、テトラヒドロフラン（7 mL）の混合物に酢酸（182 μL）を加えた後、室温で20分間攪拌した。飽和炭酸水素ナトリウム水溶液を加えて反応を停止した後、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）で精製し、標記目的化合物（184 mg, 34%）を白色固体として得た。
1H NMR (300 MHz, CDCl3) δ ppm 1.05-1.36 (m, 5H), 1.41-1.92 (m, 5H), 2.08 (d, J=12.1 Hz, 1H), 2.46 (s, 3H), 3.80 (s, 3H), 4.52 (d, J=6.1 Hz, 1H), 4.61 (dd, J=7.2, 6.1 Hz, 1H), 6.48 (d, J=9.1 Hz, 2H), 7.54 (s, 1H), 7.79 (d, J=8.7 Hz, 2H), 8.70 (s, 1H). (5) 4-{[(5-chloro-3-methylthieno [2,3-c] pyridin-2-yl) (cyclohexyl) methyl] amino} methyl benzoate (5-chloro-3-methylthieno [2,3 -c] Pyridin-2-yl) (cyclohexyl) methanol (370 mg), 4-methylmorpholine N-oxide (332 mg) and acetonitrile (7 mL) were added with tetrapropylammonium perruthenate (44 mg). The mixture was stirred at room temperature for 3 days and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give a yellow solid (187 mg). To a mixture of the obtained solid (187 mg), methyl 4-aminobenzoate (115 mg), triethylamine (708 μL) and dichloromethane (3 mL) was added a 1.0 M dichloromethane solution (762 μL) of titanium (IV) chloride. And then stirred at room temperature overnight. 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 to give a dark red oil. Acetic acid (182 μL) 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.
1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.05-1.36 (m, 5H), 1.41-1.92 (m, 5H), 2.08 (d, J = 12.1 Hz, 1H), 2.46 (s, 3H), 3.80 (s, 3H), 4.52 (d, J = 6.1 Hz, 1H), 4.61 (dd, J = 7.2, 6.1 Hz, 1H), 6.48 (d, J = 9.1 Hz, 2H), 7.54 (s, 1H) , 7.79 (d, J = 8.7 Hz, 2H), 8.70 (s, 1H).
（６）4-{[(5-クロロ-3-メチルチエノ[2,3-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}安息香酸
　4-{[(5-クロロ-3-メチルチエノ[2,3-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}安息香酸メチル（184 mg）、テトラヒドロフラン（3 mL）およびメタノール（3 mL）の混合物に1規定水酸化ナトリウム水溶液（1.72 mL）を加えた後、80℃で終夜攪拌した。1規定塩酸水溶液（1.72 mL）を加えて反応液を中和した後、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）で精製し、標記目的化合物（33 mg, 18%）およびメチルエステル（125 mg, 68%）を得た。回収されたメチルエステル（125 mg）を上記と同様の操作で加水分解して、標記目的化合物（109 mg）を白色固体として得た。
1H NMR (300 MHz, CDCl3) δ ppm 1.06-1.38 (m, 4H), 1.51-1.92 (m, 6H), 2.07 (d, J=16.3 Hz, 1H), 2.46 (s, 3H), 4.50-4.72 (m, 2H), 6.49 (d, J=8.7 Hz, 2H), 7.55 (d, J=0.8 Hz, 1H), 7.83 (d, J-=8.7 Hz, 2H), 8.70 (d, J=0.8 Hz, 1H). (6) 4-{[(5-chloro-3-methylthieno [2,3-c] pyridin-2-yl) (cyclohexyl) methyl] amino} benzoic acid 4-{[(5-chloro-3-methylthieno [ 2,3-c] Pyridin-2-yl) (cyclohexyl) methyl] amino} methyl benzoate (184 mg), tetrahydrofuran (3 mL) and methanol (3 mL) in 1N aqueous sodium hydroxide (1.72 mL) ) And then stirred at 80 ° C. overnight. 1N Hydrochloric acid aqueous solution (1.72 mL) was added to neutralize the reaction mixture, 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 (33 mg, 18%) and methyl ester (125 mg, 68%). The recovered methyl ester (125 mg) was hydrolyzed in the same manner as above to give the title object compound (109 mg) as a white solid.
1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.06-1.38 (m, 4H), 1.51-1.92 (m, 6H), 2.07 (d, J = 16.3 Hz, 1H), 2.46 (s, 3H), 4.50 -4.72 (m, 2H), 6.49 (d, J = 8.7 Hz, 2H), 7.55 (d, J = 0.8 Hz, 1H), 7.83 (d, J- = 8.7 Hz, 2H), 8.70 (d, J = 0.8 Hz, 1H).
（７）3-{[(4-{[(5-クロロ-3-メチルチエノ[2,3-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}フェニル)カルボニル](メチル)アミノ}プロパン酸エチル
　4-{[(5-クロロ-3-メチルチエノ[2,3-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}安息香酸（142 mg）、3-(メチルアミノ)プロパン酸エチル（54 mg）、1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩（79 mg）、1-ヒドロキシベンゾトリアゾール一水和物（63 mg）、トリエチルアミン（57 μL）およびN,N-ジメチルホルムアミド（3 mL）の混合物を室温で終夜攪拌した。混合物を水に加えて反応を停止させた後、酢酸エチルで抽出した。抽出液を水および飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）で精製し、標記目的化合物（167 mg, 92%）を無色油状物として得た。
1H NMR (300 MHz, CDCl3) δ ppm 1.06-1.92 (m, 13H), 2.07 (m, 1H), 2.45 (s, 3H), 2.60 (t, J=7.2 Hz, 2H), 2.99 (s, 3H), 3.69 (t, J=7.0 Hz, 2H), 4.10 (q, J=7.2 Hz, 2H), 4.32 (d, J=5.7 Hz, 1H), 4.56 (dd, J=7.2, 5.7 Hz, 1H), 6.48 (d, J=8.7 Hz, 2H), 7.20 (d, J=8.7 Hz, 2H), 7.54 (d, J=0.8 Hz, 1H), 8.70 (d, J=0.8 Hz, 1H). (7) 3-{[(4-{[(5-Chloro-3-methylthieno [2,3-c] pyridin-2-yl) (cyclohexyl) methyl] amino} phenyl) carbonyl] (methyl) amino} propane Ethyl 4-{[(5-chloro-3-methylthieno [2,3-c] pyridin-2-yl) (cyclohexyl) methyl] amino} benzoic acid (142 mg), ethyl 3- (methylamino) propanoate (54 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (79 mg), 1-hydroxybenzotriazole monohydrate (63 mg), triethylamine (57 μL) and N, N- A mixture of dimethylformamide (3 mL) was stirred at room temperature overnight. The mixture was added to water to stop the reaction, and extracted with ethyl acetate. The extract was washed with water and 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 (167 mg, 92%) as a colorless oil.
1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.06-1.92 (m, 13H), 2.07 (m, 1H), 2.45 (s, 3H), 2.60 (t, J = 7.2 Hz, 2H), 2.99 (s , 3H), 3.69 (t, J = 7.0 Hz, 2H), 4.10 (q, J = 7.2 Hz, 2H), 4.32 (d, J = 5.7 Hz, 1H), 4.56 (dd, J = 7.2, 5.7 Hz , 1H), 6.48 (d, J = 8.7 Hz, 2H), 7.20 (d, J = 8.7 Hz, 2H), 7.54 (d, J = 0.8 Hz, 1H), 8.70 (d, J = 0.8 Hz, 1H ).
（８）3-{[(4-{[(5-クロロ-3-メチルチエノ[2,3-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}フェニル)カルボニル](メチル)アミノ}プロパン酸
　3-{[(4-{[(5-クロロ-3-メチルチエノ[2,3-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}フェニル)カルボニル](メチル)アミノ}プロパン酸エチル（167 mg）、テトラヒドロフラン（3 mL）およびエタノール（3 mL）の混合物に1規定水酸化ナトリウム水溶液（634 μL）を加え、室温で100分間攪拌した後、減圧下濃縮した。残渣を水に溶解した後、1規定塩酸水溶液（634 μL）を加えた。生じた析出物をろ取し、標記目的化合物（137 mg, 87%）を白色固体として得た。
1H NMR (300 MHz, CDCl3) δ ppm 1.06-1.32 (m, 5H), 1.58 (d, J=11.3 Hz, 1H), 1.65-1.90 (m, 4H), 2.07 (d, J=11.3 Hz, 1H), 2.45 (s, 3H), 2.66 (t, J=6.2 Hz, 2H), 3.02 (s, 3H), 3.69 (t, J=6.6 Hz, 2H), 4.56 (d, J=7.2 Hz, 1H), 6.47 (d, J=8.7 Hz, 2H), 7.22 (d, J=8.7 Hz, 2H), 7.54 (d, J=0.8 Hz, 1H), 8.70 (d, J=0.8 Hz, 1H). (8) 3-{[(4-{[(5-Chloro-3-methylthieno [2,3-c] pyridin-2-yl) (cyclohexyl) methyl] amino} phenyl) carbonyl] (methyl) amino} propane Acid 3-{[(4-{[(5-Chloro-3-methylthieno [2,3-c] pyridin-2-yl) (cyclohexyl) methyl] amino} phenyl) carbonyl] (methyl) amino} propanoate (167 mg), tetrahydrofuran (3 mL), and ethanol (3 mL) were added with 1N aqueous sodium hydroxide solution (634 μL), stirred at room temperature for 100 minutes, and concentrated under reduced pressure. The residue was dissolved in water, and 1N aqueous hydrochloric acid (634 μL) was added. The resulting precipitate was collected by filtration to give the title object compound (137 mg, 87%) as a white solid.
1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.06-1.32 (m, 5H), 1.58 (d, J = 11.3 Hz, 1H), 1.65-1.90 (m, 4H), 2.07 (d, J = 11.3 Hz , 1H), 2.45 (s, 3H), 2.66 (t, J = 6.2 Hz, 2H), 3.02 (s, 3H), 3.69 (t, J = 6.6 Hz, 2H), 4.56 (d, J = 7.2 Hz , 1H), 6.47 (d, J = 8.7 Hz, 2H), 7.22 (d, J = 8.7 Hz, 2H), 7.54 (d, J = 0.8 Hz, 1H), 8.70 (d, J = 0.8 Hz, 1H ).
実施例11
3-{[(4-{[(5-クロロ-3-メチルチエノ[2,3-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}フェニル)カルボニル](メチル)アミノ}プロパン酸 Example 11
3-{[(4-{[(5-Chloro-3-methylthieno [2,3-c] pyridin-2-yl) (cyclohexyl) methyl] amino} phenyl) carbonyl] (methyl) amino} propanoic acid
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000011
　実施例10の(8)で合成した3-{[(4-{[(5-クロロ-3-メチルチエノ[2,3-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}フェニル)カルボニル](メチル)アミノ}プロパン酸（５８ｍｇ）を高速液体クロマトグラフィー（カラム：ＣＨＩＲＡＬＰＡＫ ＡＤ（５０ｍｍＩＤ×５００ｍｍＬ、ダイセル化学工業製）、移動相：２－プロパノール／ギ酸（１０００／１、ｖ／ｖ）、流速：６０ｍＬ／ｍｉｎ、カラム温度：３０℃）を用いて分画した。上記の高速液体クロマトグラフィー条件にて保持時間が１５分から１８分の光学活性体を含有する分画液を減圧下濃縮した後、残渣を酢酸エチルに溶かした。その溶液を水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮して標記目的化合物の光学活性体（２５ｍｇ）を白色固体として得た。
HPLC-MS:m/z=500.2(M+1); Rt=1.07 min 3-{[(4-{[(5-Chloro-3-methylthieno [2,3-c] pyridin-2-yl) (cyclohexyl) methyl] amino} phenyl) carbonyl synthesized in Example 10 (8) ] (Methyl) amino} propanoic acid (58 mg) was subjected to high performance liquid chromatography (column: CHIRALPAK AD (50 mm ID × 500 mm L, manufactured by Daicel Chemical Industries), mobile phase: 2-propanol / formic acid (1000/1, v / v), Fractionation was performed using a flow rate of 60 mL / min and a column temperature of 30 ° C. The fraction solution containing the optically active substance with a retention time of 15 to 18 minutes under the above-mentioned high performance liquid chromatography conditions was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound as an optically active substance (25 mg) as a white solid.
HPLC-MS: m / z = 500.2 (M + 1); Rt = 1.07 min
実施例12
3-{[(4-{[(5-クロロ-3-メチルチエノ[2,3-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}フェニル)カルボニル](メチル)アミノ}プロパン酸 Example 12
3-{[(4-{[(5-Chloro-3-methylthieno [2,3-c] pyridin-2-yl) (cyclohexyl) methyl] amino} phenyl) carbonyl] (methyl) amino} propanoic acid
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012
　実施例10の(8)で合成した3-{[(4-{[(5-クロロ-3-メチルチエノ[2,3-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}フェニル)カルボニル](メチル)アミノ}プロパン酸（５８ｍｇ）を高速液体クロマトグラフィー（カラム：ＣＨＩＲＡＬＰＡＫ ＡＤ（５０ｍｍＩＤ×５００ｍｍＬ、ダイセル化学工業製）、移動相：２－プロパノール／ギ酸（１０００／１、ｖ／ｖ）、流速：６０ｍＬ／ｍｉｎ、カラム温度：３０℃）を用いて分画した。上記の高速液体クロマトグラフィー条件にて保持時間が２１分から２４分の光学活性体を含有する分画液を減圧下濃縮した後、残渣を酢酸エチルに溶かした。その溶液を水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮して標記目的化合物の光学活性体（２２ｍｇ）を白色固体として得た。
HPLC-MS:m/z=500.2(M+1); Rt=1.07 min 3-{[(4-{[(5-Chloro-3-methylthieno [2,3-c] pyridin-2-yl) (cyclohexyl) methyl] amino} phenyl) carbonyl synthesized in Example 10 (8) ] (Methyl) amino} propanoic acid (58 mg) was subjected to high performance liquid chromatography (column: CHIRALPAK AD (50 mm ID × 500 mm L, manufactured by Daicel Chemical Industries), mobile phase: 2-propanol / formic acid (1000/1, v / v), Fractionation was performed using a flow rate of 60 mL / min and a column temperature of 30 ° C. A fraction solution containing an optically active substance having a retention time of 21 to 24 minutes under the above-mentioned high performance liquid chromatography conditions was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound as an optically active substance (22 mg) as a white solid.
HPLC-MS: m / z = 500.2 (M + 1); Rt = 1.07 min
実施例13
3-{[(6-{[(6-クロロ-3-メチルチエノ[3,2-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸 Example 13
3-{[(6-{[(6-Chloro-3-methylthieno [3,2-c] pyridin-2-yl) (cyclohexyl) methyl] amino} pyridin-3-yl) carbonyl] (methyl) amino} Propanoic acid
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013
（１）1-(4,6-ジクロロピリジン-3-イル)エタノン
　4,6-ジクロロニコチン酸（10 g）のテトラヒドロフラン（80 mL）溶液に塩化オキサリル（5.4 mL）とN,N-ジメチルホルムアミド（1滴）を加えた後、室温で2時間攪拌した。混合物を減圧下濃縮して白色固体を得た。得られた固体のN,N-ジメチルアセトアミド（80 mL）溶液にN,O-ジメチルヒドロキシルアミン塩酸塩（7.6 g）を加えた後、室温で3日間攪拌した。水を加えて反応を停止した後、酢酸エチルで抽出した。抽出液を飽和塩化アンモニウム水溶液および飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し、減圧下濃縮して橙色油状物（10.9 g）を得た。得られた油状物（10.9 g）のテトラヒドロフラン（80 mL）溶液に0℃でメチルマグネシウムブロミドの3.0 Mテトラヒドロフラン溶液（35 mL）を加えた後、1時間攪拌した。飽和塩化アンモニウム水溶液を加えて反応を停止した後、酢酸エチルで抽出した。抽出液を水および飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）で精製し、標記目的化合物（6.28 g, 63%）を無色油状物として得た。
1H NMR (300 MHz, CDCl3) δ ppm 2.68 (s, 3H), 7.45 (s, 1H), 8.62 (s, 1H). (1) 1- (4,6-Dichloropyridin-3-yl) ethanone To a solution of 4,6-dichloronicotinic acid (10 g) in tetrahydrofuran (80 mL) was added oxalyl chloride (5.4 mL) and N, N-dimethylformamide. (1 drop) was added and stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to give a white solid. N, O-dimethylhydroxylamine hydrochloride (7.6 g) was added to a solid N, N-dimethylacetamide (80 mL) solution, and the mixture was stirred at room temperature for 3 days. The reaction was stopped by adding water, followed by extraction with ethyl acetate. The extract was washed with saturated aqueous ammonium chloride solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give an orange oil (10.9 g). To a solution of the obtained oil (10.9 g) in tetrahydrofuran (80 mL) was added a 3.0 M solution of methylmagnesium bromide in tetrahydrofuran (35 mL) at 0 ° C., and the mixture was stirred for 1 hr. Saturated aqueous ammonium chloride solution was added to stop the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with water and 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 (6.28 g, 63%) as a colorless oil.
1 H NMR (300 MHz, CDCl 3 ) δ ppm 2.68 (s, 3H), 7.45 (s, 1H), 8.62 (s, 1H).
（２）6-クロロ-3-メチルチエノ[3,2-c]ピリジン-2-カルバルデヒド
　1-(4,6-ジクロロピリジン-3-イル)エタノン（6.28 g）、チオグリコール酸エチル（3.98 mL）およびN,N-ジメチルホルムアミド（50 mL）の混合物に炭酸カリウム（13.7 g）を加え、50℃で終夜攪拌した。水を加えて反応を停止した後、酢酸エチルで抽出した。抽出液を水および飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し、減圧下濃縮して白色固体を得た。得られた固体と塩化カルシウム（7.32 g）、テトラヒドロフラン（60 mL）およびエタノール（60 mL）の混合物に0℃で水素化ホウ素ナトリウム（5.00 g）を加えた後、室温で終夜攪拌した。飽和塩化アンモニウム水溶液を加えて反応を停止した後、減圧下濃縮してテトラヒドロフランとエタノールを除き、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し、減圧下濃縮して白色固体（5.49 g）を得た。得られた固体（5.49 g）、二酸化マンガン（11 g）およびテトラヒドロフラン（70 mL）の混合物を50℃で終夜攪拌した。二酸化マンガンをろ別した後、ろ液を減圧下濃縮し、標記目的化合物（5.39 g, 77%）を微黄色固体として得た。
1H NMR (300 MHz, CDCl3) δ ppm 2.87 (s, 3H), 7.83 (d, J=0.8 Hz, 1H), 8.98 (d, J=0.8 Hz, 1H), 10.33 (s, 1H). (2) 6-chloro-3-methylthieno [3,2-c] pyridine-2-carbaldehyde 1- (4,6-dichloropyridin-3-yl) ethanone (6.28 g), ethyl thioglycolate (3.98 mL) ) And N, N-dimethylformamide (50 mL) was added potassium carbonate (13.7 g), and the mixture was stirred at 50 ° C. overnight. The reaction was stopped by adding water, followed by extraction with ethyl acetate. The extract was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a white solid. To a mixture of the obtained solid, calcium chloride (7.32 g), tetrahydrofuran (60 mL) and ethanol (60 mL) was added sodium borohydride (5.00 g) at 0 ° C., and the mixture was stirred at room temperature overnight. Saturated aqueous ammonium chloride solution was added to stop the reaction, and the mixture was concentrated under reduced pressure to remove tetrahydrofuran and ethanol, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a white solid (5.49 g). A mixture of the obtained solid (5.49 g), manganese dioxide (11 g) and tetrahydrofuran (70 mL) was stirred at 50 ° C. overnight. After manganese dioxide was filtered off, the filtrate was concentrated under reduced pressure to give the title object compound (5.39 g, 77%) as a pale yellow solid.
1 H NMR (300 MHz, CDCl 3 ) δ ppm 2.87 (s, 3H), 7.83 (d, J = 0.8 Hz, 1H), 8.98 (d, J = 0.8 Hz, 1H), 10.33 (s, 1H).
（３）(6-クロロ-3-メチルチエノ[3,2-c]ピリジン-2-イル)(シクロヘキシル)メタノール
　6-クロロ-3-メチルチエノ[3,2-c]ピリジン-2-カルバルデヒド（1.06 g）のテトラヒドロフラン（20 mL）溶液に0℃でシクロヘキシルマグネシウムブロミドの1.0 Mテトラヒドロフラン溶液（7.5 mL）を加え、1時間攪拌した。飽和塩化アンモニウム水溶液を加えて反応を停止した後、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）で精製し、標記目的化合物（928 mg, 63%）を黄色固体として得た。
1H NMR (300 MHz, CDCl3) δ ppm 0.90-1.94 (m, 10H), 2.13 (d, J=12.9 Hz, 1H), 2.18 (d, J=3.4 Hz, 1H), 2.40 (s, 3H), 4.83 (dd, J=8.0, 2.7 Hz, 1H), 7.74 (d, J=0.8 Hz, 1H), 8.68 (d, J=0.8 Hz, 1H). (3) (6-Chloro-3-methylthieno [3,2-c] pyridin-2-yl) (cyclohexyl) methanol 6-chloro-3-methylthieno [3,2-c] pyridine-2-carbaldehyde (1.06 To a tetrahydrofuran (20 mL) solution of g) was added a 1.0 M tetrahydrofuran solution (7.5 mL) of cyclohexylmagnesium bromide at 0 ° C., and the mixture was stirred for 1 hour. Saturated aqueous ammonium chloride 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 (928 mg, 63%) as a yellow solid.
1 H NMR (300 MHz, CDCl 3 ) δ ppm 0.90-1.94 (m, 10H), 2.13 (d, J = 12.9 Hz, 1H), 2.18 (d, J = 3.4 Hz, 1H), 2.40 (s, 3H ), 4.83 (dd, J = 8.0, 2.7 Hz, 1H), 7.74 (d, J = 0.8 Hz, 1H), 8.68 (d, J = 0.8 Hz, 1H).
（４）(6-クロロ-3-メチルチエノ[3,2-c]ピリジン-2-イル)(シクロヘキシル)メタノン
　(6-クロロ-3-メチルチエノ[3,2-c]ピリジン-2-イル)(シクロヘキシル)メタノール（928 mg）のアセトニトリル（10 mL）およびテトラヒドロフラン（10 mL）の混合物に0℃でデス－マーチンペルヨージナン（1.46 g）を加え、40分間攪拌した。飽和炭酸水素ナトリウム水溶液およびチオ硫酸ナトリウム水溶液を加えて反応を停止した後、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）で精製し、標記目的化合物（723 mg, 78%）を黄色固体として得た。
1H NMR (300 MHz, CDCl3) δ ppm 1.22-1.53 (m, 5H), 1.69-1.81 (m, 1H), 1.81-1.92 (m, 2H), 1.97 (d, J=11.7 Hz, 2H), 2.79 (s, 3H), 2.96 (tt, J=11.2, 3.4 Hz, 1H), 7.78 (d, J=0.8 Hz, 1H), 8.93 (d, J=0.8 Hz, 1H). (4) (6-Chloro-3-methylthieno [3,2-c] pyridin-2-yl) (cyclohexyl) methanone (6-Chloro-3-methylthieno [3,2-c] pyridin-2-yl) ( Dess-Martin periodinane (1.46 g) was added to a mixture of cyclohexyl) methanol (928 mg) in acetonitrile (10 mL) and tetrahydrofuran (10 mL) at 0 ° C. and stirred for 40 minutes. Saturated aqueous sodium hydrogen carbonate solution and aqueous sodium thiosulfate solution were 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 (723 mg, 78%) as a yellow solid.
1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.22-1.53 (m, 5H), 1.69-1.81 (m, 1H), 1.81-1.92 (m, 2H), 1.97 (d, J = 11.7 Hz, 2H) , 2.79 (s, 3H), 2.96 (tt, J = 11.2, 3.4 Hz, 1H), 7.78 (d, J = 0.8 Hz, 1H), 8.93 (d, J = 0.8 Hz, 1H).
（５）6-{[(6-クロロ-3-メチルチエノ[3,2-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}ピリジン-3-カルボン酸メチル
　(6-クロロ-3-メチルチエノ[3,2-c]ピリジン-2-イル)(シクロヘキシル)メタノン（723 mg）、6-アミノピリジン-3-カルボン酸メチル（449 mg）、トリエチルアミン（2.74 mL）およびジクロロメタン（12 mL）の混合物に塩化チタン（IV）の1.0 Mジクロロメタン溶液（2.95 mL）を加えた後、室温で終夜攪拌した。飽和炭酸水素ナトリウム水溶液を加えて反応を停止した後、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し、減圧下濃縮して暗赤色油状物を得た。得られた油状物、シアノ水素化ホウ素ナトリウム（309 mg）、テトラヒドロフラン（12 mL）の混合物に酢酸（704 μL）を加えた後、室温で30分間攪拌した。飽和炭酸水素ナトリウム水溶液を加えて反応を停止した後、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）で精製し、標記目的化合物（391 mg, 37%）を得た。
1H NMR (300 MHz, CDCl3) δ ppm 1.03-1.90 (m, 10H), 2.04 (s, 1H), 2.54 (s, 3H), 3.83 (s 3H), 5.11 (t, J=8.0 Hz, 1H), 5.20 (d, J=7.2 Hz, 1H), 6.27 (dd, J=8.7, 0.8 Hz, 1H), 7.66 (d, J=0.8 Hz, 1H), 7.92 (dd, J=9.1, 2.3 Hz, 1H), 8.68 (d, J=1.1 Hz, 1H), 8.72 (dd, J=2.3, 0.8 Hz, 1H). (5) methyl 6-{[(6-chloro-3-methylthieno [3,2-c] pyridin-2-yl) (cyclohexyl) methyl] amino} pyridine-3-carboxylate (6-chloro-3-methylthieno A mixture of [3,2-c] pyridin-2-yl) (cyclohexyl) methanone (723 mg), methyl 6-aminopyridine-3-carboxylate (449 mg), triethylamine (2.74 mL) and dichloromethane (12 mL) To the mixture was added a 1.0 M dichloromethane solution (2.95 mL) of titanium (IV) chloride, and the mixture was stirred at room temperature overnight. 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 to give a dark red oil. Acetic acid (704 μL) was added to a mixture of the obtained oil, sodium cyanoborohydride (309 mg), and tetrahydrofuran (12 mL), and the mixture was stirred at room temperature for 30 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 (391 mg, 37%).
1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.03-1.90 (m, 10H), 2.04 (s, 1H), 2.54 (s, 3H), 3.83 (s 3H), 5.11 (t, J = 8.0 Hz, 1H), 5.20 (d, J = 7.2 Hz, 1H), 6.27 (dd, J = 8.7, 0.8 Hz, 1H), 7.66 (d, J = 0.8 Hz, 1H), 7.92 (dd, J = 9.1, 2.3 Hz, 1H), 8.68 (d, J = 1.1 Hz, 1H), 8.72 (dd, J = 2.3, 0.8 Hz, 1H).
（６）6-{[(6-クロロ-3-メチルチエノ[3,2-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}ピリジン-3-カルボン酸
　6-{[(6-クロロ-3-メチルチエノ[3,2-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}ピリジン-3-カルボン酸メチル（391 mg）、テトラヒドロフラン（7 mL）およびメタノール（7 mL）の混合物に1規定水酸化ナトリウム水溶液（1.82 mL）を加えた後、80℃で終夜攪拌した。1規定塩酸水溶液（1.82 mL）を加えて反応液を中和した後、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）で精製し、標記目的化合物（323 mg, 85%）を微黄色固体として得た。
1H NMR (300 MHz, CDCl3) δ ppm 1.04-2.02 (m, 10H), 2.14 (d, J= 11.0 Hz, 1H), 2.55 (s, 3H), 4.73 (br s, 1H), 6.28 (d, J=8.7 Hz, 1H), 7.64 (s, 1H), 8.08 (dd, J=8.9, 2.1 Hz, 1H), 8.69 (d, J=0.8 Hz, 1H), 8.75 (d, J=1.9 Hz, 1H). (6) 6-{[(6-Chloro-3-methylthieno [3,2-c] pyridin-2-yl) (cyclohexyl) methyl] amino} pyridine-3-carboxylic acid 6-{[(6-chloro- 1 to a mixture of methyl 3-methylthieno [3,2-c] pyridin-2-yl) (cyclohexyl) methyl] amino} pyridine-3-carboxylate (391 mg), tetrahydrofuran (7 mL) and methanol (7 mL) A normal aqueous sodium hydroxide solution (1.82 mL) was added, and the mixture was stirred at 80 ° C. overnight. 1N Hydrochloric acid aqueous solution (1.82 mL) was added to neutralize the reaction mixture, 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 (323 mg, 85%) as a pale-yellow solid.
1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.04-2.02 (m, 10H), 2.14 (d, J = 11.0 Hz, 1H), 2.55 (s, 3H), 4.73 (br s, 1H), 6.28 ( d, J = 8.7 Hz, 1H), 7.64 (s, 1H), 8.08 (dd, J = 8.9, 2.1 Hz, 1H), 8.69 (d, J = 0.8 Hz, 1H), 8.75 (d, J = 1.9 Hz, 1H).
（７）3-{[(6-{[(6-クロロ-3-メチルチエノ[3,2-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸エチル
　6-{[(6-クロロ-3-メチルチエノ[3,2-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}ピリジン-3-カルボン酸（159 mg）、3-(メチルアミノ)プロパン酸エチル（60 mg）、1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩（88 mg）、1-ヒドロキシベンゾトリアゾール一水和物（70 mg）、トリエチルアミン（64 μL）およびN,N-ジメチルホルムアミド（3 mL）の混合物を室温で終夜攪拌した。混合物を水にあけて反応を停止させた後、酢酸エチルで抽出した。抽出液を水および飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）で精製し、標記目的化合物（171 mg, 87%）を無色アモルファス固体として得た。
1H NMR (300 MHz, CDCl3) δ ppm 1.04-1.89 (m, 13H), 2.00-2.15 (m, 1H), 2.53 (s, 3H), 2.62 (t, J=6.8 Hz, 2H), 3.03 (s, 3H), 3.71 (t, J=6.8 Hz, 2H), 4.12 (q, J=7.2 Hz, 2H), 5.03 (d, J=4.9 Hz, 2H), 6.27 (d, J=8.7 Hz, 1H), 7.46 (dd, J=8.5, 2.5 Hz, 1H), 7.66 (d, J=0.8 Hz, 1H), 8.18 (d, J=2.3 Hz, 1H), 8.67 (d, J=0.8 Hz, 1H). (7) 3-{[(6-{[(6-Chloro-3-methylthieno [3,2-c] pyridin-2-yl) (cyclohexyl) methyl] amino} pyridin-3-yl) carbonyl] (methyl ) Amino} ethyl propanoate 6-{[(6-chloro-3-methylthieno [3,2-c] pyridin-2-yl) (cyclohexyl) methyl] amino} pyridine-3-carboxylic acid (159 mg), 3 -Ethyl (methylamino) propanoate (60 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (88 mg), 1-hydroxybenzotriazole monohydrate (70 mg), triethylamine ( 64 μL) and N, N-dimethylformamide (3 mL) were stirred at room temperature overnight. The mixture was poured into water to stop the reaction, and extracted with ethyl acetate. The extract was washed with water and 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 (171 mg, 87%) as a colorless amorphous solid.
1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.04-1.89 (m, 13H), 2.00-2.15 (m, 1H), 2.53 (s, 3H), 2.62 (t, J = 6.8 Hz, 2H), 3.03 (s, 3H), 3.71 (t, J = 6.8 Hz, 2H), 4.12 (q, J = 7.2 Hz, 2H), 5.03 (d, J = 4.9 Hz, 2H), 6.27 (d, J = 8.7 Hz , 1H), 7.46 (dd, J = 8.5, 2.5 Hz, 1H), 7.66 (d, J = 0.8 Hz, 1H), 8.18 (d, J = 2.3 Hz, 1H), 8.67 (d, J = 0.8 Hz , 1H).
（８）3-{[(6-{[(6-クロロ-3-メチルチエノ[3,2-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸
　3-{[(6-{[(6-クロロ-3-メチルチエノ[3,2-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸エチル（171 mg）、テトラヒドロフラン（2 mL）およびエタノール（2 mL）の混合物に1規定水酸化ナトリウム水溶液（664 μL）を加え、室温で2.5時間攪拌した後、減圧下濃縮した。残渣を水に溶解した後、1規定塩酸水溶液（664 μL）を加えた。生じた析出物をろ取し、標記目的化合物（157 mg, 94%）を白色固体として得た。
1H NMR (300 MHz, CDCl3) δ ppm 0.98-1.39 (m, 5H), 1.54 (d, J=12.1 Hz, 1H), 1.61-1.96 (m, 4H), 2.12 (d, J=10.9 Hz, 1H), 2.52 (s, 3H), 2.66 (t, J=5.8 Hz, 2H), 3.08 (s, 3H), 3.76 (br s, 2H), 4.53-4.67 (m, 1H), 6.26 (d, J=9.0 Hz, 1H), 7.54 (dd, J=8.9, 0.9 Hz, 1H), 7.67 (d, J=0.8 Hz, 1H), 8.05 (d, J=1.1 Hz, 1H), 8.68 (d, J=0.8 Hz, 1H). (8) 3-{[(6-{[(6-Chloro-3-methylthieno [3,2-c] pyridin-2-yl) (cyclohexyl) methyl] amino} pyridin-3-yl) carbonyl] (methyl ) Amino} propanoic acid 3-{[(6-{[(6-chloro-3-methylthieno [3,2-c] pyridin-2-yl) (cyclohexyl) methyl] amino} pyridin-3-yl) carbonyl] To a mixture of (methyl) amino} ethyl propanoate (171 mg), tetrahydrofuran (2 mL) and ethanol (2 mL) was added 1N aqueous sodium hydroxide solution (664 μL), and the mixture was stirred at room temperature for 2.5 hr. Concentrated. The residue was dissolved in water, and 1N aqueous hydrochloric acid solution (664 μL) was added. The resulting precipitate was collected by filtration to give the title object compound (157 mg, 94%) as a white solid.
1 H NMR (300 MHz, CDCl 3 ) δ ppm 0.98-1.39 (m, 5H), 1.54 (d, J = 12.1 Hz, 1H), 1.61-1.96 (m, 4H), 2.12 (d, J = 10.9 Hz , 1H), 2.52 (s, 3H), 2.66 (t, J = 5.8 Hz, 2H), 3.08 (s, 3H), 3.76 (br s, 2H), 4.53-4.67 (m, 1H), 6.26 (d , J = 9.0 Hz, 1H), 7.54 (dd, J = 8.9, 0.9 Hz, 1H), 7.67 (d, J = 0.8 Hz, 1H), 8.05 (d, J = 1.1 Hz, 1H), 8.68 (d , J = 0.8 Hz, 1H).
実施例14
3-{[(6-{[(6-クロロ-3-メチルチエノ[3,2-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸 Example 14
3-{[(6-{[(6-Chloro-3-methylthieno [3,2-c] pyridin-2-yl) (cyclohexyl) methyl] amino} pyridin-3-yl) carbonyl] (methyl) amino} Propanoic acid
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000014
　実施例13の(8)で合成した3-{[(6-{[(6-クロロ-3-メチルチエノ[3,2-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸（８５ｍｇ）を高速液体クロマトグラフィー（カラム：ＣＨＩＲＡＬＰＡＫ ＡＤ（５０ｍｍＩＤ×５００ｍｍＬ、ダイセル化学工業製）、移動相：ヘキサン／２－プロパノール／ギ酸（７００／３００／１、ｖ／ｖ／ｖ）、流速：８０ｍＬ／ｍｉｎ、カラム温度：３０℃）を用いて分画した。上記の高速液体クロマトグラフィー条件にて保持時間が３２分から４５分の光学活性体を含有する分画液を減圧下濃縮した後、残渣を酢酸エチルに溶かした。その溶液を水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮して標記目的化合物の光学活性体（３５ｍｇ）を白色固体として得た。
HPLC-MS:m/z=50１.4(M+1); Rt=0.96 min 3-{[(6-{[(6-Chloro-3-methylthieno [3,2-c] pyridin-2-yl) (cyclohexyl) methyl] amino} pyridine-3 synthesized in (8) of Example 13 -Yl) carbonyl] (methyl) amino} propanoic acid (85 mg) was subjected to high performance liquid chromatography (column: CHIRALPAK AD (50 mm ID × 500 mm L, manufactured by Daicel Chemical Industries), mobile phase: hexane / 2-propanol / formic acid (700/300). / 1, v / v / v), flow rate: 80 mL / min, column temperature: 30 ° C.). The fraction solution containing the optically active substance having a retention time of 32 minutes to 45 minutes under the above high performance liquid chromatography conditions was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound as an optically active substance (35 mg) as a white solid.
HPLC-MS: m / z = 501.4 (M + 1); Rt = 0.96 min
実施例15
3-{[(6-{[(6-クロロ-3-メチルチエノ[3,2-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸 Example 15
3-{[(6-{[(6-Chloro-3-methylthieno [3,2-c] pyridin-2-yl) (cyclohexyl) methyl] amino} pyridin-3-yl) carbonyl] (methyl) amino} Propanoic acid
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
　実施例13の(8)で合成した3-{[(6-{[(6-クロロ-3-メチルチエノ[3,2-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸（８５ｍｇ）を高速液体クロマトグラフィー（カラム：ＣＨＩＲＡＬＰＡＫ ＡＤ（５０ｍｍＩＤ×５００ｍｍＬ、ダイセル化学工業製）、移動相：ヘキサン／２－プロパノール／ギ酸（７００／３００／１、ｖ／ｖ／ｖ）、流速：８０ｍＬ／ｍｉｎ、カラム温度：３０℃）を用いて分画した。上記の高速液体クロマトグラフィー条件にて保持時間が６５分から９０分の光学活性体を含有する分画液を減圧下濃縮した後、残渣を酢酸エチルに溶かした。その溶液を水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮して標記目的化合物の光学活性体（３８ｍｇ）を白色固体として得た。
HPLC-MS:m/z=50１.4(M+1); Rt=0.96 min 3-{[(6-{[(6-Chloro-3-methylthieno [3,2-c] pyridin-2-yl) (cyclohexyl) methyl] amino} pyridine-3 synthesized in (8) of Example 13 -Yl) carbonyl] (methyl) amino} propanoic acid (85 mg) was subjected to high performance liquid chromatography (column: CHIRALPAK AD (50 mm ID × 500 mm L, manufactured by Daicel Chemical Industries), mobile phase: hexane / 2-propanol / formic acid (700/300). / 1, v / v / v), flow rate: 80 mL / min, column temperature: 30 ° C.). A fraction solution containing an optically active substance having a retention time of 65 minutes to 90 minutes under the above high performance liquid chromatography conditions was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound as an optically active substance (38 mg) as a white solid.
HPLC-MS: m / z = 501.4 (M + 1); Rt = 0.96 min
実施例16
3-{[(4-{[(6-クロロ-3-メチルチエノ[3,2-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}フェニル)カルボニル](メチル)アミノ}プロパン酸 Example 16
3-{[(4-{[(6-Chloro-3-methylthieno [3,2-c] pyridin-2-yl) (cyclohexyl) methyl] amino} phenyl) carbonyl] (methyl) amino} propanoic acid
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016
（１）4-{[(6-クロロ-3-メチルチエノ[3,2-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}安息香酸メチル
　実施例13の(4)で合成した(6-クロロ-3-メチルチエノ[3,2-c]ピリジン-2-イル)(シクロヘキシル)メタノン（278 mg）、4-アミノ安息香酸メチル（172 mg）、トリエチルアミン（1.06 mL）およびジクロロメタン（6 mL）の混合物に塩化チタン（IV）の1.0 Mジクロロメタン溶液（1.14 mL）を加えた後、室温で終夜攪拌した。飽和炭酸水素ナトリウム水溶液を加えて反応を停止した後、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し、減圧下濃縮して暗褐色油状物を得た。得られた油状物、シアノ水素化ホウ素ナトリウム（119 mg）、テトラヒドロフラン（10 mL）の混合物に酢酸（271 μL）を加えた後、室温で2時間攪拌した。飽和炭酸水素ナトリウム水溶液を加えて反応を停止した後、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）で精製し、標記目的化合物（259 mg, 64%）を桃色油状物として得た。
1H NMR (300 MHz, CDCl3) δ ppm 1.05-1.92 (m, 10H), 2.03-2.14 (m, 1H), 2.53 (s, 3H), 3.80 (s, 3H), 4.48 (d, J=5.7 Hz, 1H), 4.57 (dd, J=7.2, 5.7 Hz, 1H), 6.46-6.53 (m, 2H), 7.63 (d, J=1.1 Hz, 1H), 7.76-7.82 (m, 2H), 8.68 (d, J=0.8 Hz, 1H). (1) Methyl 4-{[(6-chloro-3-methylthieno [3,2-c] pyridin-2-yl) (cyclohexyl) methyl] amino} benzoate Synthesized in Example 13, (4) (6 -Chloro-3-methylthieno [3,2-c] pyridin-2-yl) (cyclohexyl) methanone (278 mg), methyl 4-aminobenzoate (172 mg), triethylamine (1.06 mL) and dichloromethane (6 mL) To the mixture was added a 1.0 M dichloromethane solution (1.14 mL) of titanium (IV) chloride, and the mixture was stirred at room temperature overnight. 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 to give a dark brown oil. Acetic acid (271 μL) was added to a mixture of the obtained oil, sodium cyanoborohydride (119 mg), and tetrahydrofuran (10 mL), and the mixture was stirred at room temperature for 2 hr. 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 (259 mg, 64%) as a pink oil.
1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.05-1.92 (m, 10H), 2.03-2.14 (m, 1H), 2.53 (s, 3H), 3.80 (s, 3H), 4.48 (d, J = 5.7 Hz, 1H), 4.57 (dd, J = 7.2, 5.7 Hz, 1H), 6.46-6.53 (m, 2H), 7.63 (d, J = 1.1 Hz, 1H), 7.76-7.82 (m, 2H), 8.68 (d, J = 0.8 Hz, 1H).
（２）4-{[(6-クロロ-3-メチルチエノ[3,2-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}安息香酸
　4-{[(6-クロロ-3-メチルチエノ[3,2-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}安息香酸メチル（259 mg）、テトラヒドロフラン（5 mL）およびメタノール（5 mL）の混合物に1規定水酸化ナトリウム水溶液（1.82 mL）を加えた後、80℃で終夜攪拌した。1規定塩酸水溶液（1.82 mL）を加えて反応液を中和した後、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）で精製し、標記目的化合物（212 mg, 85%）を無色アモルファス固体として得た。
1H NMR (300 MHz, CDCl3) δ ppm 1.08-1.91 (m, 10H), 2.01-2.14 (m, 1H), 2.54 (s, 3H), 4.49-4.66 (m, 2H), 6.50 (d, J=9.0 Hz, 2H), 7.64 (d, J=0.8 Hz, 1H), 7.83 (d, J=9.0 Hz, 2H), 8.69 (d, J=0.8 Hz, 1H). (2) 4-{[(6-Chloro-3-methylthieno [3,2-c] pyridin-2-yl) (cyclohexyl) methyl] amino} benzoic acid 4-{[(6-chloro-3-methylthieno [ 3,2-c] Pyridin-2-yl) (cyclohexyl) methyl] amino} methyl benzoate (259 mg), tetrahydrofuran (5 mL) and methanol (5 mL) in 1N aqueous sodium hydroxide (1.82 mL) ) And then stirred at 80 ° C. overnight. 1N Hydrochloric acid aqueous solution (1.82 mL) was added to neutralize the reaction mixture, 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 (212 mg, 85%) as a colorless amorphous solid.
1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.08-1.91 (m, 10H), 2.01-2.14 (m, 1H), 2.54 (s, 3H), 4.49-4.66 (m, 2H), 6.50 (d, J = 9.0 Hz, 2H), 7.64 (d, J = 0.8 Hz, 1H), 7.83 (d, J = 9.0 Hz, 2H), 8.69 (d, J = 0.8 Hz, 1H).
（３）3-{[(4-{[(6-クロロ-3-メチルチエノ[3,2-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}フェニル)カルボニル](メチル)アミノ}プロパン酸エチル
　4-{[(6-クロロ-3-メチルチエノ[3,2-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}安息香酸（121 mg）、3-(メチルアミノ)プロパン酸エチル（46 mg）、1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩（67 mg）、1-ヒドロキシベンゾトリアゾール１水和物（54 mg）、トリエチルアミン（49 μL）およびN,N-ジメチルホルムアミド（3 mL）の混合物を室温で終夜攪拌した。混合物を水にあけて反応を停止させた後、酢酸エチルで抽出した。抽出液を水および飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）で精製し、標記目的化合物（118 mg, 77%）を無色油状物として得た。
1H NMR (300 MHz, CDCl3) δ ppm 1.07-1.93 (m, 13H), 2.02-2.14 (m, 1H), 2.52 (s, 3H), 2.56-2.67 (m, 2H), 2.99 (s, 3H), 3.69 (t, J=7.2 Hz, 2H), 4.08-4.19 (m, 2H), 4.29 (d, J=4.9 Hz, 1H), 4.51 (dd, J=7.3, 5.8 Hz, 1H), 6.48 (d, J=8.7 Hz, 2H), 7.20 (d, J=8.7 Hz, 2H), 7.64 (s, 1H), 8.68 (s, 1H). (3) 3-{[(4-{[(6-Chloro-3-methylthieno [3,2-c] pyridin-2-yl) (cyclohexyl) methyl] amino} phenyl) carbonyl] (methyl) amino} propane Acid ethyl 4-{[(6-chloro-3-methylthieno [3,2-c] pyridin-2-yl) (cyclohexyl) methyl] amino} benzoic acid (121 mg), ethyl 3- (methylamino) propanoate (46 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (67 mg), 1-hydroxybenzotriazole monohydrate (54 mg), triethylamine (49 μL) and N, N- A mixture of dimethylformamide (3 mL) was stirred at room temperature overnight. The mixture was poured into water to stop the reaction, and extracted with ethyl acetate. The extract was washed with water and 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 (118 mg, 77%) as a colorless oil.
1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.07-1.93 (m, 13H), 2.02-2.14 (m, 1H), 2.52 (s, 3H), 2.56-2.67 (m, 2H), 2.99 (s, 3H), 3.69 (t, J = 7.2 Hz, 2H), 4.08-4.19 (m, 2H), 4.29 (d, J = 4.9 Hz, 1H), 4.51 (dd, J = 7.3, 5.8 Hz, 1H), 6.48 (d, J = 8.7 Hz, 2H), 7.20 (d, J = 8.7 Hz, 2H), 7.64 (s, 1H), 8.68 (s, 1H).
（４）3-{[(4-{[(6-クロロ-3-メチルチエノ[3,2-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}フェニル)カルボニル](メチル)アミノ}プロパン酸
　3-{[(4-{[(6-クロロ-3-メチルチエノ[3,2-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}フェニル)カルボニル](メチル)アミノ}プロパン酸エチル（118 mg）、テトラヒドロフラン（2 mL）およびエタノール（2 mL）の混合物に1規定水酸化ナトリウム水溶液（448 μL）を加え、室温で3時間攪拌した後、減圧下濃縮した。残渣を水に溶解した後、1規定塩酸水溶液（448 μL）を加えた。生じた析出物をろ取し、標記目的化合物（102 mg, 91%）を白色固体として得た。
1H NMR (300 MHz, CDCl3) δ ppm 1.03-1.31 (m, 5H), 1.57 (d, J=10.5 Hz, 1H), 1.62-1.88 (m, 4H), 2.01-2.13 (m, 1H), 2.51 (s, 3H), 2.59 (t, J=6.0 Hz, 2H), 2.98 (s, 3H), 3.66 (t, J=6.2 Hz, 2H), 4.50 (d, J=7.2 Hz, 1H), 6.47 (d, J=8.7 Hz, 2H), 7.20 (d, J=8.7 Hz, 2H), 7.62 (s, 1H), 8.67 (d, J=0.8 Hz, 1H). (4) 3-{[(4-{[(6-Chloro-3-methylthieno [3,2-c] pyridin-2-yl) (cyclohexyl) methyl] amino} phenyl) carbonyl] (methyl) amino} propane Acid 3-{[(4-{[(6-Chloro-3-methylthieno [3,2-c] pyridin-2-yl) (cyclohexyl) methyl] amino} phenyl) carbonyl] (methyl) amino} propanoic acid ethyl 1N Aqueous sodium hydroxide solution (448 μL) was added to a mixture of (118 mg), tetrahydrofuran (2 mL) and ethanol (2 mL), stirred at room temperature for 3 hours, and concentrated under reduced pressure. The residue was dissolved in water, and 1N aqueous hydrochloric acid solution (448 μL) was added. The resulting precipitate was collected by filtration to give the title object compound (102 mg, 91%) as a white solid.
1 H NMR (300 MHz, CDCl 3 ) δ ppm 1.03-1.31 (m, 5H), 1.57 (d, J = 10.5 Hz, 1H), 1.62-1.88 (m, 4H), 2.01-2.13 (m, 1H) , 2.51 (s, 3H), 2.59 (t, J = 6.0 Hz, 2H), 2.98 (s, 3H), 3.66 (t, J = 6.2 Hz, 2H), 4.50 (d, J = 7.2 Hz, 1H) , 6.47 (d, J = 8.7 Hz, 2H), 7.20 (d, J = 8.7 Hz, 2H), 7.62 (s, 1H), 8.67 (d, J = 0.8 Hz, 1H).
実施例17
3-{[(4-{[(6-クロロ-3-メチルチエノ[3,2-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}フェニル)カルボニル](メチル)アミノ}プロパン酸 Example 17
3-{[(4-{[(6-Chloro-3-methylthieno [3,2-c] pyridin-2-yl) (cyclohexyl) methyl] amino} phenyl) carbonyl] (methyl) amino} propanoic acid
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
　実施例16の(4)で合成した3-{[(4-{[(6-クロロ-3-メチルチエノ[3,2-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}フェニル)カルボニル](メチル)アミノ}プロパン酸（２０ｍｇ）を高速液体クロマトグラフィー（カラム：ＣＨＩＲＡＬＰＡＫ ＡＤ（５０ｍｍＩＤ×５００ｍｍＬ、ダイセル化学工業製）、移動相：ヘキサン／２－プロパノール／ギ酸（７００／３００／１、ｖ／ｖ／ｖ）、流速：８０ｍＬ／ｍｉｎ、カラム温度：３０℃）を用いて分画した。上記の高速液体クロマトグラフィー条件にて保持時間が３５分から４４分の光学活性体を含有する分画液を減圧下濃縮した後、残渣を酢酸エチルに溶かした。その溶液を水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮して標記目的化合物の光学活性体（１０ｍｇ）を白色固体として得た。
HPLC-MS:m/z=500.3(M+1); Rt=1.02 min 3-{[(4-{[(6-Chloro-3-methylthieno [3,2-c] pyridin-2-yl) (cyclohexyl) methyl] amino} phenyl) carbonyl synthesized in Example 16 (4) ] (Methyl) amino} propanoic acid (20 mg) was subjected to high performance liquid chromatography (column: CHIRALPAK AD (50 mm ID × 500 mm L, manufactured by Daicel Chemical Industries), mobile phase: hexane / 2-propanol / formic acid (700/300/1, v / V / v), flow rate: 80 mL / min, column temperature: 30 ° C.). The fraction solution containing the optically active substance having a retention time of 35 minutes to 44 minutes under the above high performance liquid chromatography conditions was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound as an optically active substance (10 mg) as a white solid.
HPLC-MS: m / z = 500.3 (M + 1); Rt = 1.02 min
実施例18
3-{[(4-{[(6-クロロ-3-メチルチエノ[3,2-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}フェニル)カルボニル](メチル)アミノ}プロパン酸 Example 18
3-{[(4-{[(6-Chloro-3-methylthieno [3,2-c] pyridin-2-yl) (cyclohexyl) methyl] amino} phenyl) carbonyl] (methyl) amino} propanoic acid
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018
　実施例16の(4)で合成した3-{[(4-{[(6-クロロ-3-メチルチエノ[3,2-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}フェニル)カルボニル](メチル)アミノ}プロパン酸を高速液体クロマトグラフィー（カラム：ＣＨＩＲＡＬＰＡＫ ＡＤ（５０ｍｍＩＤ×５００ｍｍＬ、ダイセル化学工業製）、移動相：ヘキサン／２－プロパノール／ギ酸（７００／３００／１、ｖ／ｖ／ｖ）、流速：８０ｍＬ／ｍｉｎ、カラム温度：３０℃）を用いて分画する。上記の高速液体クロマトグラフィー条件にて出現する２つのピークのうち保持時間が大きい方の光学活性体を含有する分画液を飽和炭酸水素ナトリウム水溶液で洗浄し、水層を酢酸エチルで抽出する。有機層を合わせて飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥する。ろ過操作後、ろ液を濃縮し標記目的化合物の光学活性体を得る。 3-{[(4-{[(6-Chloro-3-methylthieno [3,2-c] pyridin-2-yl) (cyclohexyl) methyl] amino} phenyl) carbonyl synthesized in Example 16 (4) ] (Methyl) amino} propanoic acid was subjected to high performance liquid chromatography (column: CHIRALPAK® AD (50 mm ID × 500 mm L, manufactured by Daicel Chemical Industries), mobile phase: hexane / 2-propanol / formic acid (700/300/1, v / v / v), flow rate: 80 mL / min, column temperature: 30 ° C.). Of the two peaks appearing under the above-mentioned high performance liquid chromatography conditions, 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.
実験例１
　以下の方法により、本発明化合物のグルカゴン結合阻害作用を評価した。
（１）ヒトグルカゴン受容体遺伝子のクローニング
　ヒトグルカゴン受容体遺伝子のクローニングは、ヒト膵臓Marathon-ready cDNA (クロンテック)を鋳型とし、以下のプライマーセットを用いたPCR反応により行った。
ＧＧＲ-Ｕ：
５’－ＡＡＴＡＧＡＡＴＴＣＡＴＧＣＣＣＣＣＣＴＧＣＣＡＧＣＣＡＣＡＧ－３’　（配列番号：１）
ＧＧＲ-Ｌ：
５’－ＣＴＡＡＧＣＧＧＣＣＧＣＴＣＡＧＡＡＧＧＧＧＣＴＣＴＣＡＧＣＣＡＡＴＣＴ－３’　（配列番号：２）
　PCR反応は、Advantage 2ポリメラーゼ(クロンテック)を用いて添付のプロトコールに従って行った。得られたPCR産物をアガロースゲル(1%)電気泳動し、グルカゴン受容体遺伝子を含む約1.4 kbのDNA断片をゲルから回収した後、制限酵素EcoRIおよびNotIで消化した。制限酵素処理したDNAをアガロースゲル(1%)で電気泳動し、約1.4 kbのDNA断片を回収し、制限酵素EcoRIおよびNotIで消化したプラスミドpMSRαneoへライゲーションして、ヒト型グルカゴン受容体発現プラスミドＤＮＡ「pMSRαneo /hGCGR」を作製した。挿入断片の塩基配列を確認し、目的の配列と一致していることを確認した。 Experimental example 1
The 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)
PCR reaction was performed using Advantage 2 polymerase (Clontech) according to the attached protocol. 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 pMSRαneo digested with restriction enzymes EcoRI and NotI, and human glucagon receptor expression plasmid DNA “PMSRαneo / hGCGR” was prepared. The base sequence of the inserted fragment was confirmed and confirmed to be consistent with the target sequence.
（２）グルカゴン受容体膜タンパク質の調製
　ヒト型グルカゴン受容体の発現は、FreeStyle CHO Expression System（インビトロジェン社）を用いて行った。FreeStyle CHO Expression Systemに添付されたマニュアルに従い、上記（１）で作製したヒト型グルカゴン受容体発現プラスミドＤＮＡ「pMSRαneo /hGCGR」を用いてFreeStyle CHO細胞による一過性発現を行った。上記ＤＮＡをトランスフェクションした後、３７℃、８％ＣＯ２、１２５ｒｐｍで２日間振とう培養を行った。２４００ｍｌの培養液に対して２，０００ｒｐｍで１０分間遠心分離を行い、細胞を回収した。回収した細胞をＰＢＳで洗浄後、ホモジネート用緩衝液［１０ｍＭ　ＮａＨＣＯ３（ｐＨ７．４）、１ｍＭ　ＥＤＴＡ、コンプリートＥＤＴＡ－フリー（ロッシュ社、１　ｔａｂｌｅｔ／５０ｍｌ）］に懸濁し、ポリトロン細胞破砕装置（キネマティカ社）で細胞を破砕した。破砕液を２，０００ｒｐｍで１０分間遠心分離を行って上清を回収し、その上清を３５，０００ｒｐｍで６０分間遠心分離後、沈殿を緩衝液［２０ｍＭ　Ｔｒｉｓ－ＨＣｌ（ｐＨ７．４）、５ｍＭ　ＥＤＴＡ、コンプリート　ＥＤＴＡ－フリー（ロッシュ社、１　ｔａｂｌｅｔ／５０ｍｌ）］に懸濁して、４５２ｍｇのグルカゴン受容体膜タンパク質を得た。 (2) Preparation of Glucagon Receptor Membrane Protein Human glucagon receptor was expressed using FreeStyle CHO Expression System (Invitrogen). According to the manual attached to the FreeStyle CHO Expression System, transient expression by FreeStyle CHO cells was performed using the human-type glucagon receptor expression plasmid DNA “pMSRαneo / hGCGR” prepared in (1) above. After transfection with the above DNA, shaking culture was performed at 37 ° C., 8% CO 2 , 125 rpm for 2 days. The cells were collected by centrifuging the 2400 ml culture at 2,000 rpm for 10 minutes. 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.
（３）グルカゴン結合阻害活性の測定
　９６穴プレート（コーニング社）の各ウェルに、反応用緩衝液［５０ｍＭ　Ｔｒｉｓ－ＨＣｌ（ｐＨ７．４）、５ｍＭ　ＥＧＴＡ、５ｍＭ　塩化マグネシウム、０．１％　ＢＳＡ、０．００５％　Ｔｗｅｅｎ２０］で１００μｇ／ｍｌに希釈したグルカゴン受容体膜タンパク質溶液を５０μｌ、反応用緩衝液で化合物濃度４０μＭになるよう調製した０．４％ＤＭＳＯを含む試験化合物溶液を２５μl、および反応用緩衝液で２００ｐＭに希釈した放射性標識したグルカゴン（［１２５Ｉ］－Ｒｅｃｅｐｔｏｒ　Ｇｒａｄｅ　Ｇｌｕｃａｇｏｎ；パーキンエルマー社）２５μｌを添加して反応を開始した。室温で９０分間静置した後、反応プレートから９６穴ユニフィルターＧＦ／Ｃ　プレート（パーキンエルマー社）にセルハーベスター（パーキンエルマー社）を用いて反応溶液を移し、吸引してフィルター上に膜画分を捕集した。フィルターは、予め０．３％ポリエチレンイミンに浸して標識リガンドの非特異的吸着を防いだ。フィルターを反応用緩衝液で４回洗浄後、４２℃で２時間乾燥し、各ウェルに２５μｌのシンチレータ（ＭｉｃｒｏＳｃｉｎｔ０；パーキンエルマー社）を添加し、マイクロプレートシンチレーションカウンター（ＴｏｐＣｏｕｎｔ　ＮＸＴＴＭ；パーキンエルマー社）で放射活性を測定した。 (3) Measurement of glucagon binding inhibitory activity In each well of a 96-well plate (Corning), a reaction buffer [50 mM Tris-HCl (pH 7.4), 5 mM EGTA, 5 mM magnesium chloride, 0.1% BSA, 0 50 μl of glucagon receptor membrane protein solution diluted to 100 μg / ml with .005% Tween 20], 25 μl of test compound solution containing 0.4% DMSO prepared to a compound concentration of 40 μM with reaction buffer, and for reaction The reaction was started by adding 25 μl of radiolabeled glucagon ([ 125 I] -Receptor Grade Glucagon; PerkinElmer) diluted to 200 pM with buffer. After leaving at room temperature for 90 minutes, the 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 μl of scintillator (MicroScint0; PerkinElmer) was added to each well, and a microplate scintillation counter (TopCount NXT ™ ; PerkinElmer) The radioactivity was measured at
　０．４％ＤＭＳＯのみを添加したウェルの反応率を阻害率０％、非標識のグルカゴン（終濃度１μＭ）を添加したウェルの反応率を阻害率１００％として、試験化合物（１０μＭ；０．４％ＤＭＳＯ溶液を含む）を添加したウェルの阻害率（％）を算出した。結果を表１に示す。 The test compound (10 μM; 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 μM) as 100% inhibition rate. Inhibition rate (%) of wells containing% DMSO solution was calculated. The results are shown in Table 1.
Figure JPOXMLDOC01-appb-T000019
Figure JPOXMLDOC01-appb-T000019
　上記のように、本発明化合物は、優れたグルカゴン結合阻害作用を有することが示された。 As described above, it was shown that the compound of the present invention has an excellent glucagon binding inhibitory action.
実験例２　グルカゴン誘導性血糖上昇抑制作用試験（ラット）
　飽食SD ラット（雄性、7-9週齢）を絶食し、試験化合物(３－６ｍｇ／ｋｇ体重)を含む0.5％メチルセルロース懸濁液（化合物投与群、１群１０－１３匹）または0.5％メチルセルロース懸濁液（化合物非投与群、１群１２匹）を経口投与し、60分後にグルカゴン（15 μg/kg体重、ノボノルディスクファーマ（株））を皮下投与した。グルカゴン投与20 分後にラット尾静脈より採血し、血糖を自己検査用グルコースキットACCU-CHEK（ロシュ・ダイアグノスティックス（株））を用いて測定した。また、無処置群（１群５匹）として、化合物非投与群にグルカゴンを投与しない場合のラットの血糖を上記と同様にして測定した。
　化合物非投与群および化合物投与群の血糖と無処置群の血糖との差をそれぞれ算出し、「化合物非投与群の血糖と無処置群の血糖との差」を100%とした場合の「化合物投与群の血糖と無処置群の血糖との差」の百分率を「血糖上昇率（％ of control）」として求めた。結果を表２に示す。 Experimental Example 2 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 μg / 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.). In addition, as an untreated group (5 mice per group), blood glucose of rats when no glucagon was administered to the compound non-administered group was measured in the same manner as described above.
Calculate the difference between the blood glucose of the compound non-administered group and the compound-administered group and the blood glucose of the non-treated group, respectively. The percentage of the “difference between the blood glucose in the administration group and the blood glucose in the non-treatment group” was determined as the “% increase in blood glucose (% of control)”. The results are shown in Table 2.
Figure JPOXMLDOC01-appb-T000020
Figure JPOXMLDOC01-appb-T000020
　上記のように、本発明化合物は、優れた血糖上昇抑制作用を有することが示された。 As described above, it was shown that the compound of the present invention has an excellent blood glucose elevation inhibitory action.
製剤例１（カプセルの製造）　　　　　　　　
　１）実施例１の化合物　　　　　　３０　ｍｇ
　２）微粉末セルロース　　　　　　１０　ｍｇ
　３）乳糖　　　　　　　　　　　　１９　ｍｇ
　４）ステアリン酸マグネシウム　　　１　ｍｇ
　　　　　　　　　　　　　　　計　６０　ｍｇ
 
　１）、２）、３）および４）を混合して、ゼラチンカプセルに充填する。 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.
製剤例２（錠剤の製造）
　１）実施例１の化合物　　　　　　　　　　　　　　 ３０　ｇ
　２）乳糖　　　　　　　　　　　　　　　　　　　　 ５０　ｇ
　３）トウモロコシデンプン　　　　　　　　　　　　 １５　ｇ
　４）カルボキシメチルセルロースカルシウム　　　　 ４４　ｇ
　５）ステアリン酸マグネシウム　　　　　　　　　　　 １　ｇ
　　　　　　　　　　　　１０００錠　　　　　計　 １４０　ｇ
 
　１）、２）、３）の全量および３０ｇの４）を水で練合し、真空乾燥後、整粒を行う。この整粒末に１４ｇの４）および１ｇの５）を混合し、打錠機により打錠する。このようにして、１錠あたり実施例１の化合物３０ｍｇを含有する錠剤１０００錠を得る。 Formulation Example 2 (Manufacture of tablets)
1) Compound of Example 1 30 g
2) Lactose 50 g
3) Corn starch 15 g
4) Carboxymethylcellulose calcium 44 g
5) Magnesium stearate 1 g
1000 tablets total 140 g

The total amount of 1), 2) and 3) and 30 g of 4) are kneaded with water, and after vacuum drying, the particles are sized. 14 g of 4) and 1 g of 5) are mixed with the sized powder, and tableted with a tableting machine. In this way, 1000 tablets containing 30 mg of the compound of Example 1 per tablet are obtained.
　本発明化合物は、グルカゴン拮抗作用を有し、糖尿病等の予防または治療に有用である。 The compound of the present invention has glucagon antagonism and is useful for the prevention or treatment of diabetes and the like.
　本出願は、日本で出願された特願２００９－２０５２９４を基礎としており、その内容は本明細書にすべて包含される。 This application is based on Japanese Patent Application No. 2009-205294 filed in Japan, the contents of which are incorporated in full herein.

Claims (13)

  1. 　3-{[(6-{[(5-クロロ-1-メチル-1H-インドール-2-イル)(シクロヘキシル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸またはその塩。 3-{[(6-{[(5-Chloro-1-methyl-1H-indol-2-yl) (cyclohexyl) methyl] amino} pyridin-3-yl) carbonyl] (methyl) amino} propanoic acid or its salt.
  2. 　3-{[(6-{[シクロヘキシル(5-フルオロ-1-メチル-1H-インドール-2-イル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸またはその塩。 3-{[(6-{[cyclohexyl (5-fluoro-1-methyl-1H-indol-2-yl) methyl] amino} pyridin-3-yl) carbonyl] (methyl) amino} propanoic acid or a salt thereof.
  3. 　3-{[(6-{[(5-クロロ-1-メチル-1H-インドール-2-イル)(シクロペンチル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸またはその塩。 3-{[(6-{[(5-Chloro-1-methyl-1H-indol-2-yl) (cyclopentyl) methyl] amino} pyridin-3-yl) carbonyl] (methyl) amino} propanoic acid or its salt.
  4. 　3-{[(4-{[(5-クロロ-3-メチルチエノ[2,3-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}フェニル)カルボニル](メチル)アミノ}プロパン酸またはその塩。 3-{[(4-{[(5-Chloro-3-methylthieno [2,3-c] pyridin-2-yl) (cyclohexyl) methyl] amino} phenyl) carbonyl] (methyl) amino} propanoic acid or its salt.
  5. 　3-{[(6-{[(6-クロロ-3-メチルチエノ[3,2-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}ピリジン-3-イル)カルボニル](メチル)アミノ}プロパン酸またはその塩。 3-{[(6-{[(6-Chloro-3-methylthieno [3,2-c] pyridin-2-yl) (cyclohexyl) methyl] amino} pyridin-3-yl) carbonyl] (methyl) amino} Propanoic acid or its salt.
  6. 　3-{[(4-{[(6-クロロ-3-メチルチエノ[3,2-c]ピリジン-2-イル)(シクロヘキシル)メチル]アミノ}フェニル)カルボニル](メチル)アミノ}プロパン酸またはその塩。 3-{[(4-{[(6-Chloro-3-methylthieno [3,2-c] pyridin-2-yl) (cyclohexyl) methyl] amino} phenyl) carbonyl] (methyl) amino} propanoic acid or its salt.
  7. 　請求項１～６のいずれか１項に記載の化合物またはその塩のプロドラッグ。 A prodrug of the compound or salt thereof according to any one of claims 1 to 6.
  8. 　請求項１～６のいずれか１項に記載の化合物またはその塩またはそのプロドラッグを含有してなる医薬。 A medicament comprising the compound according to any one of claims 1 to 6 or a salt thereof or a prodrug thereof.
  9. 　グルカゴン拮抗剤である、請求項８記載の医薬。 The medicament according to claim 8, which is a glucagon antagonist.
  10. 　糖産生抑制剤である、請求項８記載の医薬。 The medicament according to claim 8, which is a sugar production inhibitor.
  11. 　糖尿病の予防または治療剤である、請求項８記載の医薬。 The medicament according to claim 8, which is a preventive or therapeutic agent for diabetes.
  12. 　請求項１～６のいずれか１項に記載の化合物またはその塩またはそのプロドラッグを哺乳動物に投与することを特徴とする、該哺乳動物における糖尿病の予防または治療方法。 A method for preventing or treating diabetes in a mammal, comprising administering the compound according to any one of claims 1 to 6 or a salt thereof or a prodrug thereof to the mammal.
  13. 　糖尿病の予防または治療剤を製造するための、請求項１～６のいずれか１項に記載の化合物またはその塩またはそのプロドラッグの使用。 Use of the compound according to any one of claims 1 to 6, a salt thereof or a prodrug thereof for the manufacture of an agent for preventing or treating diabetes.
PCT/JP2010/065102 2009-09-04 2010-09-03 Heterocyclic compound WO2011027849A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2009205294 2009-09-04
JP2009-205294 2009-09-04

Publications (1)

Publication Number Publication Date
WO2011027849A1 true WO2011027849A1 (en) 2011-03-10

Family

ID=43649384

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2010/065102 WO2011027849A1 (en) 2009-09-04 2010-09-03 Heterocyclic compound

Country Status (1)

Country Link
WO (1) WO2011027849A1 (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8507533B2 (en) 2011-02-08 2013-08-13 Pfizer Inc. Glucagon receptor modulators
WO2013147026A1 (en) 2012-03-29 2013-10-03 武田薬品工業株式会社 Aromatic ring compound
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

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005511683A (en) * 2001-12-03 2005-04-28 ノボ　ノルディスク　アクティーゼルスカブ Novel glucagon antagonist
JP2006500325A (en) * 2002-06-27 2006-01-05 ノボ　ノルディスク　アクティーゼルスカブ Novel glucagon antagonist
JP2006528687A (en) * 2003-05-09 2006-12-21 メルク　エンド　カムパニー　インコーポレーテッド Benzimidazoles, compositions containing such compounds and methods of use
WO2009057784A1 (en) * 2007-11-01 2009-05-07 Takeda Pharmaceutical Company Limited Heterocyclic compound
WO2009110520A1 (en) * 2008-03-05 2009-09-11 武田薬品工業株式会社 Heterocyclic compound

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005511683A (en) * 2001-12-03 2005-04-28 ノボ　ノルディスク　アクティーゼルスカブ Novel glucagon antagonist
JP2006500325A (en) * 2002-06-27 2006-01-05 ノボ　ノルディスク　アクティーゼルスカブ Novel glucagon antagonist
JP2006528687A (en) * 2003-05-09 2006-12-21 メルク　エンド　カムパニー　インコーポレーテッド Benzimidazoles, compositions containing such compounds and methods of use
WO2009057784A1 (en) * 2007-11-01 2009-05-07 Takeda Pharmaceutical Company Limited Heterocyclic compound
WO2009110520A1 (en) * 2008-03-05 2009-09-11 武田薬品工業株式会社 Heterocyclic compound

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
US9056834B2 (en) 2010-12-23 2015-06-16 Pfizer Inc. Glucagon receptor modulators
US8507533B2 (en) 2011-02-08 2013-08-13 Pfizer Inc. Glucagon receptor modulators
US8859591B2 (en) 2011-02-08 2014-10-14 Pfizer Inc. Glucagon receptor modulators
US9073871B2 (en) 2011-02-08 2015-07-07 Pfizer Inc. Glucagon receptor modulators
US9452999B2 (en) 2011-02-08 2016-09-27 Pfizer Inc. Glucagon receptor modulators
US8927577B2 (en) 2011-07-22 2015-01-06 Pfizer Inc. Quinolinyl glucagon receptor modulators
US9139538B2 (en) 2011-07-22 2015-09-22 Pfizer Inc. Quinolinyl glucagon receptor modulators
WO2013147026A1 (en) 2012-03-29 2013-10-03 武田薬品工業株式会社 Aromatic ring compound
CN104350040A (en) * 2012-03-29 2015-02-11 武田药品工业株式会社 Aromatic ring compound
US9073864B2 (en) 2012-03-29 2015-07-07 Takeda Pharmaceutical Company Limted Aromatic ring compound

Similar Documents

Publication Publication Date Title
EP3105213B1 (en) Dihydrobenzofuran compounds useful in the treatment of diabetes and obesity
US9428470B2 (en) Heterocyclic compound
US9751878B2 (en) Tetrahydronaphthyridine somatostatin receptor 5 antagonists
JPWO2015020184A1 (en) Aromatic ring compounds
US10017487B2 (en) Fused heterocyclic compound
EP3063139B1 (en) Heterocyclic compound
WO2011027849A1 (en) Heterocyclic compound
JP6247697B2 (en) Spiroazetidine isoxazole derivatives and their use as SSTR5 antagonists
WO2016159049A1 (en) Monocyclic compound
JPWO2013147026A1 (en) Aromatic ring compounds
US20210403420A1 (en) Benzoate compound
EP1460062A1 (en) Nitrogenous cyclic ketone derivative, process for producing the same, and use
JP2004300133A (en) Amine derivative
JP2003252853A (en) Nitrogenous cyclic ketone derivative, method for producing the same, and use

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10813796

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10813796

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP