WO2009038204A1 - Nouveau composé dérivé d'un acide gras à longue chaîne et agoniste des récepteurs couplés aux protéines g qui contient le composé en tant qu'ingrédient actif - Google Patents

Nouveau composé dérivé d'un acide gras à longue chaîne et agoniste des récepteurs couplés aux protéines g qui contient le composé en tant qu'ingrédient actif Download PDF

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WO2009038204A1
WO2009038204A1 PCT/JP2008/067051 JP2008067051W WO2009038204A1 WO 2009038204 A1 WO2009038204 A1 WO 2009038204A1 JP 2008067051 W JP2008067051 W JP 2008067051W WO 2009038204 A1 WO2009038204 A1 WO 2009038204A1
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group
chlorophenyl
dichloro
acid
methyl
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PCT/JP2008/067051
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English (en)
Japanese (ja)
Inventor
Gozoh Tsujimoto
Akira Hirasawa
Yoshiyuki Takahara
Tsutomu Toma
Hidefumi Ozawa
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Pharma Frontier Co., Ltd.
Kowa Company, Ltd.
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Publication of WO2009038204A1 publication Critical patent/WO2009038204A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/19—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
    • A23L33/12—Fatty acids or derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/51—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/81—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/82—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/87—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C247/00—Compounds containing azido groups
    • C07C247/02—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C247/12—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/32—Oximes
    • C07C251/34—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C251/48—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with the carbon atom of at least one of the oxyimino groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/03—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C311/06—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms to acyclic carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0652—Cells of skeletal and connective tissues; Mesenchyme
    • C12N5/0655—Chondrocytes; Cartilage

Definitions

  • the present invention relates to a novel long-chain fatty acid derivative compound having an agonistic action on GPR 120 and Z or GPR 40, particularly a 2,2-dihaloalkanecarboxylic acid derivative compound, and these compounds or salts thereof
  • the present invention relates to a G protein-coupled receptor (GPCR) having a fatty acid as an active ingredient as a ligand, more specifically to an agonist of GPR 120 and / or GPR 40,
  • GPCR G protein-coupled receptor
  • the present invention relates to agents for treating gastrointestinal diseases, therapeutic agents for neurological disorders, therapeutic agents for mental disorders, therapeutic agents for lung diseases, therapeutic agents for pituitary hormone secretion deficiency, and lipid flavoring seasonings. Background art
  • GPR 120 and GPR 40 and their related molecules are known as G protein-coupled receptors (GPCR) having fatty acid as a ligand, and GPR 41 and GPR 40 are related molecules.
  • GPR 4 2 etc. are known.
  • the fatty acid receptor G P R 120 is present in the intestinal tract, lungs, brain, etc., and its expression is particularly prominent in the intestinal tract.
  • GPR 1 2 0 is known to have 95% amino acid identity with the 1 4 2 7 3 receptor, which is a G protein-coupled receptor.
  • GLP-1 glucagon-like peptide 1
  • CNK collagen tokinin
  • These peptides control physiological functions related to feeding behavior, for example, insulin secretion from knee cells, spleen secretion from the spleen, bile secretion from the gallbladder, It controls appetite suppression. Therefore, by administering to the body a substance that activates the function of GPR 120, prevention and treatment of diabetes due to increased secretion of insulin, treatment of digestive insufficiency by promoting digestive secretion, obesity due to anorectic effect Prevention and treatment of this is conceivable. Furthermore, these peptides are centrally involved in the maintenance of nerve cells. In addition to the intestine, GPR 1 2 0 is present in the lung, pituitary gland, adipocyte and tongue, I am doing. It is presumed that the pituitary gland promotes secretion of pituitary hormones, the fat cells promote fat differentiation, the tongue contributes to taste, and the lungs contribute to lung cell protection.
  • fatty acid 1 4 2 7 3 (GPR 1 2 0 the same meaning) in I Ri intracellular C a 2 + concentration rises to act, the intracellular c AM P generation suppression, activation of MA P kinase, adrenocorticotropic It has been known that suppression of stimulating hormone (AC TH) secretion, suppression of glycerol production from adipocytes, suppression of lipolysis, and the like occur (see, for example, WO 2004Z06 5 9 60). Therefore, it is also expected to be effective as a therapeutic agent for hypersecretion of glucocorticoid (cortisol) and adrenal and adrenal gland secreted by stimulation of ACTH from ACTH hypersecretion or adrenal gland .
  • AC TH stimulating hormone
  • the inventors of the present invention have unexpectedly analyzed the function of the GPCR gene GT 0 1 (GPR 1 2 0) polypeptide and identified compounds that act on the peptide.
  • GT 0 1 polypeptides are distributed on the surface of human intestinal secretory cells and have the function of promoting the secretion of CCK, which functions to control feeding.
  • a compound that is a ligand for GT 0 1 polypeptide has been clarified.
  • a compound for a pharmaceutical composition for treating eating disorders is proposed, and examples of such compounds include force phosphonic acid, lauric acid, myristic acid, pentadecanoin.
  • Acid palmitic acid, stearic acid, araquinic acid, behenic acid, margaric acid, noremic acid, eicosatrienoic acid, elaidic acid, petrocerinic acid, oleic acid, linolenic acid ⁇ -linolenic acid, homo- ⁇ -linolenic acid, arachidonic acid, eicosagenic acid, eicosatrienic acid, eicosapentaenoic acid, docosahexaenoic acid, linoleic acid, eicosatratraic acid, vaccenic acid, etc.
  • Fatty acids were proposed. (For example, see Japanese Patent Laid-Open No. 2 0 0 5-1 5 3 5 8)
  • G P R 40 is a 9 9 9
  • a ligand that acts on GPR 40 is expected as a prophylactic / therapeutic agent with a new mechanism of action for diabetes. (See WO 2 0 0 3 0 6 8 9 5 9)
  • the following compounds are known as fatty acid compounds useful as antidiabetic agents.
  • Inoue et al. Have hypoglycemic action, plasma insulin lowering action, and triglyceride lowering action. Diabetes, diabetic complications, hyperlipidemia or arteriosclerosis
  • the compounds represented by the following general formula, their salts, or their esters are reported to be effective for the prevention and / or treatment of diseases. (Refer to WO 2 0 0 4/1 0 3 9 4 6)
  • 12-Prom-2 2- Dichloro-dodecanoic acid, 16-bromo-2,2-dic-mouth-hexadecanoic acid, 2,2-dichloro-12-cyano-dodecanoic acid, 2,2-dichloro-12-phenoxy-dodecanoic acid, 2 , 2-diglycol -12_ (4-dioxy-phenoxy) -fatty acid compounds such as dodecanoic acid. (See W0 1 9 9 6 Z 1 5 7 8 4)
  • A is an alkyl chain having 5 to 20 carbon atoms
  • a ′ is a covalently bonded biylene or acetylene group, or an alkyl chain having 1 to 10 carbon atoms
  • B is a covalent bond, A methylene group, sulfur, oxygen or NR 1 ;
  • W is a hexyl group, a phenyl group or the like which may be substituted with various substituents;
  • GLP-1 glucagons like peptide-1
  • GLP-1 hormone is degraded in the body in a short time, so it is difficult to use GLP-1 directly for treatment. It was true. Therefore, it is important to search and develop new ligand compounds that stimulate GPR 120 and promote GLP-1 secretion.
  • GPR 120 and / or GPR 40 which use fatty acids as ligands
  • specific and effective agonist compounds have been known.
  • no agonist compound with excellent activity that can be expected to be put to practical use as a pharmaceutical has been proposed.
  • an object of the present invention is to provide a compound having excellent agonist activity with respect to GPR 1 20 and Z or GPR 40 having a fatty acid as a ligand, and further, such a compound is effective.
  • Pharmaceutical composition as an ingredient, in particular an agonist, appetite regulator containing the agonist as an active ingredient, obesity inhibitor, diabetes mellitus, spleen J3 cell differentiation and proliferation promoter, metabolic syndrome therapeutic agent It is intended to provide a therapeutic agent for digestive system diseases, a therapeutic agent for neurological disorders, a therapeutic agent for mental disorders, a therapeutic agent for lung diseases or a pituitary hormone deficiency therapeutic agent, and a lipid flavoring seasoning. Means for solving the problem
  • GPR 1 20 exists in the intestinal tract, lungs, brain, etc., so that cells possessing GPR 1 2 0 present in the intestine act on GPR 1 2 0 by fatty acids.
  • intestinal hormone peptides such as glucagon-like peptide 1 (GLP-1) and collagen tokinin (CCK) are released.
  • GLP-1 glucagon-like peptide 1
  • CNK collagen tokinin
  • the present invention provides a long-chain fatty acid derivative compound or a salt thereof such as an aralkyl carboxylic acid compound having excellent agonist activity with respect to GPR 120 and / or GPR 40, and , A pharmaceutical composition containing the compound as an active ingredient, in particular an agonist, and an appetite regulating agent containing the compound or a pharmaceutically acceptable salt thereof as an active ingredient, an obesity suppressor, diabetes treatment Agent, knee i3 cell differentiation / proliferation agent, metabolic syndrome treatment agent, digestive disease treatment agent, neurological disorder treatment agent, mental disorder treatment agent, lung disease treatment agent, pituitary hormone secretion deficiency treatment agent and the compound Alternatively, it provides a lipid-flavored seasoning containing the salt as an active ingredient.
  • the present invention will be specifically described, but the present invention is not limited thereto.
  • n means an integer from 0 to 6;
  • n means an integer from 5 to 20;
  • n means an integer of 20 or less
  • R represents a hydrogen atom or an ester residue
  • Y 1 and Y 2 are the same or different halogen atoms
  • Ring Q means a carbocyclic group which may be condensed or a heterocyclic group which may be condensed;
  • X 1, X 2 and X 3 are the same or different and each is a hydrogen atom, a halogen atom, C 4 alkyl groups, C ⁇ - 4 alkoxy groups, C 4 alkyl sulfonyl group, a halo C - 4 alkyl group , a nitro group, an amino group, a hydroxyl group, Shiano group, a mercapto group, - 4 alkylthio group, sulfonamide de group, Asechirua amino group, C j 6 alkylamino group, current events 1 - 6 alkylamino group, carboxy group, Ariruokishi A group, an aryl group, an aralkyl group, a benzoyl group, a carboxy Ci 4 alkyl group, an oxo group, a methylenedioxy group, an ethylenedioxy group or an acetoxy group;
  • R 1 represents a hydrogen atom or a C 6 _6 alkyl group ;
  • R 2 and R 3 are the same or different and each is hydrogen atom, C i_ 8 alkyl group, Ararukiru group, ⁇ Rino Rea Honoré Ke group, ⁇ reel alkynyl group, SO
  • R 4 represents an alkyl group, an aryl group or an aralkyl group
  • C OR 5 represents a C 6 alkyl group, an aryl group, an aralkyl group or an arylalkylene Or a saturated heterocycle having at least one nitrogen atom formed by R 2 and R 3 together with the adjacent nitrogen atom.
  • alkyl group may be substituted with 1 to 3 identical or different substituents selected from Group A below.
  • Aralkyl group, The rukenyl group and the allylalkynyl group may be substituted with 1 to 3 identical or different substituents selected from the following group B.
  • Halogen atom a hydroxyl group, 6 alkoxy group, amino group, C, _ 6 alkylamino group, di C - 6 Anorekiruami amino group, a carbonyl group, C - 6 alkoxy carbonyl group, Shiano group and Ashiru group;
  • Halogen atom hydroxyl group, Ji, - 6 alkoxy groups, C - 6 alkyl group, Amino groups, C i 6 alkylamino group, current events - 6 alkylamino group, a carbonyl groups, C ⁇ 6 alkoxycarbonyl group, Shiano group and Ashiru Group;
  • R 2 and X 1 may be combined with the adjacent ring Q to form a condensed ring.
  • Y 1 and Y 2 are both chlorine atoms, and ring Q is an aromatic carbocyclic group that may be condensed, a saturated carbocyclic group that may be condensed, or an aromatic heterocycle that may be condensed.
  • ring Q ′ means a phenyl group or a C 3 8 cycloalkyl group.
  • the ring Q is a phenyl group, and R is a hydrogen atom, and is represented by the following general formula (III) 4.
  • x means a halogen atom.
  • n is an integer from 6 to 1 4
  • R 2 is a hydrogen atom
  • R 3 is a C 6 alkyl group, an aralkyl group, an aryl alkenyl group, a C- 6 alkylsulfonyl group, SO 2 R 4 (where R 4 represents a C 6 alkyl group, an aryl group, or an aralkyl group.
  • R 4 represents a C 6 alkyl group, an aryl group, or an aralkyl group.
  • COR 5 R 5 represents a C j 6 alkyl group, an aryl group, an aralkyl group, or an arylalkenyl group.
  • G protein-coupled receptor using as a ligand a fatty acid containing as an active ingredient the long-chain fatty acid derivative compound according to any one of 1 to 9 above or a pharmaceutically acceptable salt thereof ) Agonist.
  • GPCR G protein-coupled receptor
  • a pharmaceutical composition comprising the long-chain fatty acid derivative compound according to any one of 1 to 9 above or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the pharmaceutical composition according to the above item 12 which is a psychiatric disorder therapeutic agent or preventive agent, a pulmonary disease therapeutic agent or prophylactic agent, or a pituitary hormone secretion deficiency therapeutic agent.
  • the long-chain fatty acid derivative compound of the present invention or a pharmaceutically acceptable salt thereof, in particular, a 2,2-dicycloalkanecarboxylic acid derivative or a pharmaceutically acceptable salt thereof is a G protein conjugate having a fatty acid as a ligand.
  • GPCR type receptor
  • the compound of the present invention can release intestinal hormone peptides such as glucagon-like peptide 1 (GLP-1) and collagen tokinin (CCK) by acting on GPR 1 2 0, and an appetite regulating agent.
  • Anti-obesity agent is effective as a therapeutic agent for insufficiency.
  • GPCR agonists having these long-chain fatty acid derivative compounds or pharmaceutically acceptable salts thereof, particularly 2,2-dicycloalkanecarboxylic acid derivative compounds as ligands more specifically GPR 12 0 agonist, GPR 40 0 agonist is a new device for diseases involving GP R12 0 and / or GPR 40, especially for diseases caused by abnormal physiological functions via GP R12 0 and ⁇ or GPR 40 It is expected to be a pharmaceutical product based on the introduction, specifically, appetite regulator, obesity suppressor, diabetes treatment agent, spleen] 3 cell differentiation and proliferation promoter, metabolic syndrome treatment agent, digestive system disease treatment agent, nerve It is effective as a disorder treatment agent, a psychiatric disorder treatment agent, a lung disease treatment agent and a pituitary hormone secretion deficiency treatment agent. In addition, since GPR 1 2 0 is involved in taste, it is expected to be effective as a lipid flavor seasoning.
  • FIG. 1 is a diagram showing the results of a ligand screening of GP R 40 according to ER ⁇ Atsei in Test Example 1 for the long-chain fatty acid derivative compound according to the present invention.
  • Figure 1 shows the results of total ERK detection by Western blotting when test compounds were stimulated using cell line TXGPR 40
  • Figure 1B shows the results when compounds were stimulated using cell line TXGPR 40.
  • An example of the detection result of phosphorylated ERK by a Western blot is shown
  • Fig. 1C shows the result of digitizing and banding the band of Fig. 1B.
  • FIG. 2 shows ERK assembly using cell line TXGPR 40 in Test Example 1.
  • FIG. 5 is a graph showing the results of the GPR 40 screening screen by
  • FIG. 3 is a graph showing the results of comparing the ERK activity of each compound using the cell line TXGPR 1 20.
  • Figure 3A shows an example of the total ERK detection result by Western blotting when stimulating the test compound using the cell line TXGPR 120
  • Figure 3B uses the cell line TXGPR 120.
  • Fig. 3C shows an example of the detection result of phosphorylated ERK by Western blotting at the time of stimulation of the test compound.
  • Fig. 3C shows the result of quantifying and graphing the band of Fig. 3B.
  • FIG. 4 is a graph showing the results of ligand screening of GP R 120 using the ERK assay using the cell line TX GP R 120 in Test Example 1.
  • the long-chain fatty acid derivative compound of the present invention has the following structural formula (I):
  • n means an integer from 0 to 6;
  • n means an integer from 5 to 20;
  • n means an integer of 20 or less
  • R represents a hydrogen atom or an ester residue
  • Y 1 and Y 2 are the same or different halogen atoms
  • Ring Q means a carbocyclic group which may be condensed or a heterocyclic group which may be condensed;
  • X 1 , X 2 and X 3 are the same or different and each represents a hydrogen atom, a halogen atom, C!- 4 alkyl group, C ⁇ - 4 alkoxy groups, C i 4 alkylsulfonyl group, Nono b C] 4 alkyl group, nitro group, amino group, hydroxyl group, Shiano group, Melka script group, C, _ 4 alkylthio group, Sulfonamide group, acetylamino group,
  • — 4 means an alkyl group, an oxo group, a methylenedioxy group, an ethylenedioxy group or an acetoxy group;
  • W is, - C -N- OR 1) - - CH (NR 2 R 3) - or - CH (N 3) - means; R 1 is hydrogen atom or a C ⁇ - means an alkyl group;
  • R 2 and R 3 are the same or different and each represents a hydrogen atom, a Ci 8 alkyl group, Aralkyl group, aryl alkenyl group, aryl alkynyl group, one so 2
  • R 4 (wherein R 4 represents a C i- 6 alkyl group, an aryl group or an aralkyl group),-COR 5 (R 5 represents.)-6 alkyl group, aryl group, aralkyl group or Or a saturated heterocycle having at least one nitrogen atom formed by R 2 and R 3 together with the adjacent nitrogen atom.
  • the alkyl group may be substituted with 1 to 3 identical or different substituents selected from Group A below.
  • the aralkyl group, the arylalkylene group, and the arylalkylinyl group may be substituted with 1 to 3 identical or different substituents selected from the following group B.
  • Halogen atom hydroxyl group, di-]- 6 alkoxy group, amino group, C- 6 alkyl amino group, di-, 6 alkylamino group, carbonyl group, Ci- 6 alkoxy carbonyl group, cyano group and acyl group;
  • Halogen atom hydroxyl group, C - 6 alkoxy group, ⁇ - 6 alkyl group, Amino group, c ⁇ - 6 alkylamino amino group, current events 1 - 6 alkylamino group, a carbonyl group,
  • R 2 and X 1 may be combined with the adjacent ring Q to form a condensed ring.
  • the meaning of terms in the present invention is as follows.
  • 6- alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butinole, isobutinole, s —butinole, t—butinole, pentinore, isopentinole, 2—methinolebutinole, neopenti / les, 1-ethinolepropinore, hexinole, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1 Methylenopentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1 monodimethylbutynole, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1 monoethylbutyl Or 2-Ethylbutyl group.
  • Preferred is a C 4 _4 alkyl group.
  • - 8 alkyl group "means a straight chain or branched alkyl Le group having 1 to 8 carbon atoms, the C, - in addition to the 6 alkyl group, and the like heptyl or Okuchiru group it can.
  • C ⁇ 4 alkyl group means a straight chain or branched alkyl Le group having 1 to 4 carbon atoms, e.g., methyl, Echiru, propyl, isopropyl, butyl , Isobutyl, S-butyl or t-butyl group.
  • halogen atom is a fluorine, chlorine, bromine or iodine atom, preferably a chlorine atom.
  • the preferred halogen atom in Y] and Y 2 is a chlorine atom
  • the preferred halogen atom in XX 2 and X 3 and the preferred halogen atom in group ⁇ and group B are chlorine, fluorine or bromine atoms.
  • Ci- 6 alkoxy group means a C 1-6 alkoxy group whose alkyl moiety is a linear or branched “., — 6 alkyl group” as defined above, For example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentoxy, isopentoxy, 2-methylbutoxy, 1-ethylpropoxy, 2-ethylpropoxy, neopentoxy, Hexinoreoxy, 4-methylenopentoxy, 3-methylpentoxy, 2-methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethyl Butoxy or 2,3-dimethylbutoxy group.
  • a C- 4 alkoxy group is preferred.
  • Alkoxy group the alkyl moiety is intended to mean a linear or branched "C] _ 4 alkyl group” having 1 to carbon atoms is a four Arukiruokishi group as defined above, for example, main butoxy , Ethoxy, propoxy, isopropoxy, butoxy, isobutoxy or t-butoxy group.
  • the - "C! 4 alkylthio group” represents a binding combined group to a sulfur atom, such as methylthio, Echiruchio, propylthio, iso-propylthio, butylthio, isobutylthio, S - butylthio Or a linear or branched alkylthio group having 1 to 4 carbon atoms such as t-butylthio group.
  • Halo C, - 4 alkyl group and, 1 to 9, preferably "Ji - 4 alkyl group” having 1 to 3 of the aforementioned definition of "halogen atom” substituted as defined above is.
  • trifluoroleolomethyl 2-funoleolethyl, 2-chloroethinole, 2-bromoechinole, 3—funoleo oral propinole, 3—black oral propinole, 4 monofluorobutyl, 4 —chlorobutyl, 2, 2, 2—tri Examples include phenol, 3,3,3-trifluoropropyl, 4,4,4 trifluorobutyl, pentafluoroethyl, or 2,2,2-trifluoroleol 1—trifluoromethylethyl, and the like. . Preferred is a trifluoromethyl group.
  • C 4, —4 alkylsulfonyl group means a straight or branched anolalkylsulfonyl group having 1 to 4 carbon atoms, such as methylesnorehoninole, ethinolesulphoninole, propinolesnorehoninole, It is a group of ipropronolesnorehoninore, butinolesnorehoninore, isobutinoresnorehoninore, s-butylsenorehoninore or t-butinoresnorehoninore.
  • the - "C! 6 alkoxycarbonyl group” means a straight or branched alkoxy group is bonded to a carbonyl group having 1 to 6 defined above carbon atoms, if example embodiment, main butoxycarbonyl, Etoxycanonbonyl, propoxycanonboninole, isopropoxycanonboninole, butoxycarbonyl, isobutoxycarbonyl, s —butoxycanononole, t —butoxycanonbonyl, pentyloxycanolebonyl, isopentyl Xicanolenobonil, 2-Methylbutoxynorebo Ninore, Neopentinorexicanoreboninole, 1—Ethenorepropoxynoreboninore, Hexinorexanoreboninore, 4—Metinorepentinorexinoreboninore , 3 — methylpentyloxycanoleboninole, 2 —
  • Ri _ 4 alkoxycarbonyl der, even more preferably a main butoxycarbonyl or e butoxycarbonyl group.
  • C, - 6 alkylamino amino group refers to one that is defined above - means "C ⁇ 6 alkyl Le group” in the substituted amino group, for example, Mechiruami Roh, Echirua Mi Bruno, pro Pyramino, Isopropyramino, Butylamino, Isobutylamino, s —Butylamino, t-Butylamino, Pentylamino, Isobentilamino, 2 —Methylbutamino, Neopentylamino, 1 —Etenorepro Pyramino, hexylamino, isohexylamino, 4-methylpentylamino, 3-methylpentylamino, 2-methylpentylamino,
  • 1-methylpentylamino, 3,3-dimethylbutylamino, 2,2-di Mono such as methyl butylamino, 1,1-dimethylbutylamino, 1,2-dimethylbutylamino, 1,3-dimethylbutylamino, 2,3-dimethylbutylamino or 2-ethylbutylamino groups is a 6 Arukirua amino groups - one C ⁇ .
  • a mono- C! _ 4 alkylamino group is a mono- C! _ 4 alkylamino group.
  • di-C 6 —alkylamino group means an amino group substituted with two identical or different r C j —e-alkyl groups as defined above, for example, dimethylamino, jetylamino, N 1 -ethylo N-methylamino, dipropylamino, dibutylamino, dipentylamino or dihexylamino groups such as di-Ci- 6 alkylamino groups.
  • di - C - a 4 alkyl Noreamino group more preferably a di one C ⁇ - a 2 alkylamino group.
  • Aryl group means an aromatic hydrocarbon group having 6 to 14 carbon atoms, for example, phenylol, naphthyl, antrinol, indenolinol, azulenyl, fluorenyl or phenanthryl. Group. Preferably, it is a phenyl group.
  • Arirukiru group 1 to 3 forces the number 6 to 1 4 of the aforementioned Ariru group having a carbon - group bonded to "C ⁇ 6 alkyl group", for example, benzyl, alpha - Nafuchinoremechiru, jS —Naphthylmethinore, Indeninolemethinore, Difueninoremethinore, Trifueninoremethinore, 1 —Fueninore, 2-Fueninore, 1-Naftinoreethinore, 2—Naftinorenocinore, 1_Fueninorepro pinole, — Hue Ninorepro pinole, 3—Phenylpropyl, 1—Naphthinorepro pinole, 2-Naphtinorepro pill, 3-Naphtinorepro pill, 1—Fuenolebutyl, 2-Fuen
  • aralkyl group in which the aryl group is a phenyl group or a naphthyl group and the alkyl group is a C- 4 alkyl group, such as a benzyl group, a naphthylmethyl group, a diphenylmethyl group, or a phenethyl group, and more preferably A benzyl group or a phenethyl group, particularly preferably a benzyl group.
  • aryloxy group means a group in which the “aryl group” is bonded to an oxygen atom, such as phenyloxy, indenyloxy, naphthyloxy, It is an aromatic hydrocarbon oxy group having 6 to 14 carbon atoms such as phenanthrenelinoxy, anthracenyloxy or phenoleorenyloxy group, and is preferably a phenyloxy or naphthyloxy group.
  • the " ⁇ reel alkenyl group”, the "Ariru group” C 2 - means a group attached to the 6 alkenyl group.
  • a "C 2 6 alkenyl group” Hetu Honoré, 1 - propenyl Ninore, 2-propenyl Ninore, 1 one Buteninore, 2 Buteninore, 3 - butene two shift, 2- Mechinore 1 one pro Peninole, 1 1 Penteninore, 2—Penteninore, 3 —Penteninore, 4 —Penteninore, 3 —Mechinolere _ 2 —Buteninole, 1 Xeninole, 3—Hexeninore, 2, 4 Xagenil or 5 — It means a linear or branched alkenyl group having 2 to 6 carbon atoms having one double bond such as hexenyl.
  • Suitable “aryl alkenyl” groups include, for example, styrinole, 3 — phenenolepronone 1 — 1-nore, 4 — phenenolepronone 3 — hen 1 — inore, 5 — Eninorev.
  • the " ⁇ reel alkynyl group”, the “Ariru group” force S - means bonded groups in the "C 2 6 alkynyl group”.
  • C 2 _ 6 alkynyl group E Chul, 1 _ pro Bulle, 2-pro Bulle, 1 Buchininore, 2 Buchuru, three to Buchininore, 1 Penchuru, 2 _ pentynyl, 3-pentynyl 4 1-penti 2-norle, 1-hexinole, 2-hexinole, 3-hexinole, 4-hexinole, 5-xinyl, etc., straight or 2 to 6 carbon atoms with one triple bond A branched alkynyl group is meant.
  • C 2 _ 6 alkynyl group for example, Hue Nino milled by wet Hee Honoré, 3 - phenylene Norepuropan one 2 - Lee emissions _ 1 - I le, 4 - full Eninorepuro Nokun one 3 - Lee down one 1 Inore , 5 — Huenino Lev. Russia Roh down one 4 - Lee down one 1 - Inore, 6 - Hue two Norepurono ⁇ 0 down one 5 - in one 1 Inore, naphth Noreechininore, 3-Nafuchinorefu.
  • the "Ashiru group”, saturated or unsaturated hydrocarbon group is optionally branched and bonded to a carbonyl group C 2 - that means the 7 aliphatic Ashiru group, or an aromatic Ashiru group.
  • Aliphatic acyl groups include, for example, acetyl, propionyl, butyrinole, isobutyrinole, no-relinole, isonole-relinole, pinole-leunole, hexanoinore, acryloyl, meta-cyl-royl, or cucumber tonoyl. Groups and the like.
  • Aromatic acyl groups include benzoyl, ⁇ -naphthoyl, and arylenocarbonyl groups such as 3-naphthoyl, halogenated arylcarbonyl groups such as 2-bromobenzoyl and 4-chlorobenzoyl groups. 1, 4, 4, 6-trimethylbenzoyl or 4 lower toluene alkyl group such as 4-toluoyl group, 4-nitrobenzoyl group, nitrogen such as 2-nitrobenzene group Aryloylcarbonyl group, 2- (methoxycarbonyl) benzoyl group such as aralkoxy carbonyl carbonyl group, aryl carbonyl group such as 4-phenyl benzoyl group, etc. Can be mentioned.
  • the - "C 3 8 cycloalkyl group” Kishinore number 3 to 8 carbon, and preferably 5 to 7 saturated cycloalkyl group, specifically, cyclopropyl, Shikurobu Chinore, cyclopentyl, cyclohexylene, cycloheteroalkyl Heptyl and cyclooctyl groups.
  • These cycloalkyl groups may contain one or two, preferably one double bond.
  • cycloalkenyl groups examples include cyclopropenenole, cyclobuteninole, cyclopenteninole, cyclopenteninole, cyclohexeninole, cyclohexagenyl (2,4-cyclohexanone 1-inore or 2 , 5 -cyclohexadiene 1 -yl group, etc.), cycloheptyl group and cyclooctyl group.
  • these cycloalkyl groups may be condensed with other cyclic groups such as a benzene ring or a heterocycle, such as indanyl, tetrahydronaphthyl, benzocycloheptyl, or 5, 6, 7, 8 It is a Trahidroy soquinolyl group.
  • cyclic groups such as a benzene ring or a heterocycle, such as indanyl, tetrahydronaphthyl, benzocycloheptyl, or 5, 6, 7, 8 It is a Trahidroy soquinolyl group.
  • the “carbocyclic group” in “optionally condensed carbocyclic group” is a saturated or unsaturated cyclic hydrocarbon group having 3 to 14 carbon atoms, specifically, the aryl group, A cycloalkyl group and a cycloalkenyl group, and these “carbocyclic groups” may be condensed carbocyclic groups condensed with carbocyclic or heterocyclic rings.
  • Examples of the “condensed carbocycle” obtained by condensing these “aryl group”, “cycloalkyl group”, and “cycloalkenyl group” include, for example, indenyl, indanyl, 1,4-dihydranaphthyl, 1, 2, 3 , 4 — Tetrahi Dronaftil (1, 2, 3, 4 -tetrahydrone 2-naphthyl, 5,6,7,8 -tetrahydr 2-naphthyl group, etc.) and perhydronaphthyl group.
  • heterocyclic group in the “heterocyclic group that may be condensed” means at least one selected from a nitrogen atom, an oxygen atom, and a sulfur atom in addition to a carbon atom, preferably 1 to 4 hetero atoms.
  • Saturated or unsaturated (including partially unsaturated and fully unsaturated) monocyclic 5-membered or 7-membered heterocycles, condensed rings of these heterocycles, or the heterocycles and benzene It means a condensed ring with a carbocyclic ring selected from cyclopentane and cyclohexane.
  • “monocyclic saturated heterocyclic group” includes pyrrolidinyl, tetrahydrodrolinole, tetrahydrodrochenyl, imidazolidinyl, virazolidinyl, 1,3-dioxanyl, 1,3-oxathiolanyl , Oxazolidinyl, thiazolidinyl, piperidinyl, piperidino, piperazur, piperazino, tetrahidrobiranyl, tetrahidrothobiranyl, dioxanyl, morpholinyl, thiomorpholinyl, 2-dioxopyridinopi Or 2, 6-dioxopiperidinyl group, etc.
  • heterocyclic group that is a condensed ring includes indyl (eg, 4-indolyl, 7-indolyl group, etc.), isoindolyl, 1,3-dihydro — 1, 3 —Doxoisoinyl drill, benzofuranyl (eg, 4-benzofuranyl, 7-benzofuranyl group, etc.), indazolinole, isobenzofuranyl, benzothiophenyl (eg, 4-benzothiophenyl, 7-ben Zothiophenyl group and the like.
  • indyl eg, 4-indolyl, 7-indolyl group, etc.
  • isoindolyl 1,3-dihydro — 1, 3 —Doxoisoinyl drill
  • benzofuranyl eg, 4-benzofuranyl, 7-benzofuranyl group, etc.
  • indazolinole isobenzofurany
  • Benzoxazolyl for example, 4-benzoxazolyl, 7-benzoxazolyl group, etc.
  • benzimidazolyl for example, 4_benzimidazolyl, 7-benzimidazolyl, etc.
  • benzothiazolinol for example, , 4 monobenzothiazolyl, 7—benzothiazolyl group, etc.
  • indolidinyl quinolinole, isoquinolinore, 1,2-dihidraw 2 —oxonolinole, quinazolinyl, quinoxalinyl, cinnolinyl, phthaladil, quinolidinyl, Prill, pteridinyl, indolinyl, isindolinyl,
  • these “aromatic heterocyclic groups” include furyl (eg, 2-furyl, 3-furyl), chenyl (eg, 2-chenyl, 3-chenyl), pyridyl.
  • furyl eg, 2-furyl, 3-furyl
  • chenyl eg, 2-chenyl, 3-chenyl
  • pyridyl eg, 2 —pyridyl, 3 —pyridyl, 4 monopyridyl
  • pyrimidinyl eg, 2 —pyrimidinyl, 4 _pyrimidinyl, 5 —pyrimidyl, 6 —pyrimidinyl
  • pyridazinyl eg, 3 —Pyridazinyl, 4-pyridazinyl
  • birazinyl eg, 2-pyrazinyl
  • pyrrolinole eg, 1 —pyrrolinole, 2—pyrrolinole, 3_pyr
  • the “ester residue” means a modifying group of a carboxyl group, and means a group that can be chemically or metabolically hydrolyzed to be chemically changed to a carboxy group.
  • bivalyloxymethyl 1 — (acetyloxy) ethyl, 1 (ethoxycarbonyloxy) ethyl, 1 (cyclohexyl) (Oxyxanolenobonyloxy) ethynole, carboxymethyl, (5-methyl-2-oxo-1, 3-dioxol-4-yl) methyl, phenyl or o-tolyl group.
  • Preferred is a C- 4 alkyl group.
  • “Saturated heterocycle” in “saturated heterocycle having at least one nitrogen atom formed together with an adjacent nitrogen atom” means, for example, at least one ring atom other than a carbon atom.
  • R 2 and X 1 may be combined with the adjacent ring Q to form a condensed ring”. Specifically, for example, R 2 and X 1 are combined together to form a methylene group, an ethylene group It may be formed.
  • Long chain in the “long chain fatty acid derivative compound” means a carboxylic acid compound having 8 to 23 carbon atoms.
  • the “pharmaceutically acceptable salt thereof” may be any salt that forms a non-toxic salt with the compound represented by the above general formula.
  • the acid that can be used to prepare a pharmaceutically acceptable acid addition salt is a pharmaceutically acceptable acid addition salt (ie, a pharmaceutically acceptable anion).
  • Salt for example, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate Salt, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, dulconate, saccharide, benzoate, methanesulfonate, ethanesulfonate, benzene Sulfonate, p-Toluene sulfonate, and acid forming pamoate.
  • Chemical bases that can be used to prepare pharmaceutically acceptable base salts are bases that form non-toxic base salts with the compound.
  • the non-toxic base salts include, but are not limited to, pharmacologically acceptable cations such as alkali metal cations (eg, potassium and sodium) and alkaline earths.
  • the compounds of the present invention include all stereoisomers (eg, cis and trans isomers) and all optical isomers (eg, R and S enantiomers) of the compound represented by formula (I), and racemates. , Diastereomers, and mixtures thereof.
  • the compounds of the invention may also exist in various tautomeric forms.
  • the present invention includes all tautomers of the compound represented by the formula (I).
  • the compounds of the present invention may contain double bonds such as olefins. When such a double bond is present, the compound of the present invention includes a cis configuration, a trans configuration, and a mixture thereof.
  • the “pharmaceutical composition” includes, in addition to a so-called “composition” composed of an active ingredient and a compounding agent as a medicine, a combination with other drugs and the like. Needless to say, the pharmaceutical composition may be used in combination with any other drug within a range that is acceptable in the medical field. Therefore, the pharmaceutical composition is for use in combination with other drugs. It can also be said to be a pharmaceutical composition.
  • n means an integer of 0 to 6, preferably an integer of 0 to 4, particularly preferably 0.
  • n represents an integer of 5 to 20, preferably an integer of 5 to 15 and preferably an integer of 8 to 15.
  • n represents an integer of 20 or less, preferably an integer of 5 to 15 and particularly preferably an integer of 8 to 15.
  • Ring Q means a condensed which may be carbocyclic or heterocyclic group, preferably Ariru group such as phenylene Le group; C 3, such as a cyclohexyl group consequent opening - 8 consequent opening alkyl group; Pi lysyl group An aromatic heterocyclic group such as a saturated heterocyclic group such as a pyrrolidinyl group. Particularly preferred are a phenyl group and a cyclohexyl group, and more preferred is a phenyl group.
  • X 1, X 2 and X 3 are the same or different and each is a hydrogen atom, a halogen atom, C j - 4 Anorekinore group, - 4 alkoxy group, c! — 4 alkylsulfonyl group, halo C i — 4 alkyl group, nitro group, amino group, hydroxyl group, cyano group, mercapto group, alkylthio group, sulfonamido group, acetylamino group,
  • Y 1 and Y 2 each represent the same or different halogen atom, preferably Y 1 and Y 2 are the same halogen atom, and more preferably Y 1 and Y 2 are both chlorine atoms.
  • R represents a hydrogen atom or an ester residue, preferably a hydrogen atom, ethyl, pivalloynoroxymethyl, 1- (acetyloxy) ethyl, 1- (ethoxycarbonyloxy) ethyl, 1- (cyclohexyl) Oxycarbonyloxy) ethyl, carboxymethyl, (5-methyl-1-2-oxo-1,3-dioxo-4-yl) methyl, phenyl, o-tolyl, etc., particularly preferably a hydrogen atom or C, - an alkyl group, most preferably a hydrogen atom.
  • R is an ester residue, in particular a C 4 -4 alkyl group
  • R is a hydrogen atom
  • it itself has an agonist activity and is also useful as a prodrug.
  • R ' is a hydrogen atom or C, it means a _ 6 alkyl group, preferably a hydrogen atom also Haji i 4 alkyl group, particularly preferably a hydrogen atom.
  • R 2 and R 3 are the same or different and each is hydrogen atom, - 8 alkyl group, Ararukiru group, ⁇ reel ⁇ Honoré en Honoré group, ⁇ reel alkynyl group, - SO 2 R 4 (where, R 4 is C j 6 alkyl group, allyl group or aralkyl group.), COR 5 (R 5 means C 26 alkyl group, aralkyl group, aralkyl group or aralkyl group), or R A saturated heterocycle having at least one nitrogen atom formed by 2 and R 3 together with the adjacent nitrogen atom.
  • the alkyl group particularly the alkyl group in R 2 and R 3
  • the alkyl group in R 2 and R 3 may be substituted with 1 to 3 identical or different substituents selected from the following dulpe A.
  • the aralkyl group, the aralkyl alkenyl group, and the aralkyl alkynyl group, particularly the aralkyl group, the aralkyl alkenyl group, and the final alkynyl group in R 2 and R 3 are 1 to 3 identical or different substituents selected from the following group B: It may be substituted with a group.
  • Halogen atom hydroxyl group, C i 6 alkoxy group, amino groups, C] - 6 alkylamino group, current events - 6 alkylamino amino group, a carbonyl groups, C 6 alkoxy carbonyl group, Shiano group and Ashiru group;
  • Halogen atom a hydroxyl group, - 6 alkoxy groups, C 6 alkyl group, Amino groups, C ⁇ - 6 alkylamino group, current events 1 - 6 alkylamino group, a carbonyl group,
  • R 2 is preferably a hydrogen atom or a C 6-6 alkyl group, particularly preferably a hydrogen atom or a C- 4 alkyl group, and more preferably a hydrogen atom.
  • R 3 represents a hydrogen atom, a C 8 alkyl group, an aralkyl group, an allyl alkenyl group, an allyl alkynyl group, S 0 2 R 4 , — COR 5 , but preferably, ⁇ — 8 alkyl group, aralkyl The group SO 2 R 4 or one COR 5 .
  • Aralkyl groups suitable as R 3 are aralkyl groups in which the aryl group such as benzyl, naphthylmethyl, diphenylmethyl or phenethyl group is a phenyl group or a naphthyl group, and the alkyl group is a C j 4 alkyl group.
  • Preferred is a benzyl or phenethyl group, and particularly preferred is benzyl. It is a group.
  • R 2 and R 3 together with the adjacent nitrogen atom form a saturated heterocyclic ring such as pyrrolidine, imidazolidine, virazolidin, piperidine, piperazine, morpholine, thiomorpholine May be.
  • R 4 is ⁇ ] - 6 alkyl group, means a Ariru group or Ararukiru group, the good Mashiku is C, 4 alkyl group or a C, _ 4 alkyl which may be substituted ⁇ Li Lumpur group with a group .
  • R 5 represents a Ci 6 alkyl group, an aryl group, an aralkyl group or an arylalkyl group, preferably a C 6 alkyl group; a phenyl group; a benzyl group, a naphthylmethyl group, a diphenylmethyl group and a phenyl: An aralkyl group selected from a group; an arylalkenyl group substituted with a phenyl group such as a styryl group;
  • R 2 and X 1 may combine together to form a methylene group or an ethylene group, and together with the adjacent ring Q to form a condensed ring.
  • the novel GPCR agonist having a fatty acid as a ligand of the present invention particularly GPR 120 agonist and / or GPR 40 agonist, contains the long-chain fatty acid derivative compound as an active ingredient. Our studies have revealed that these compounds activate (enhance) the functions of GPR 120 and Z or GPR 40.
  • these compounds act on intestinal hormone-secreting cells to release intestinal hormones, and these hormones (specifically CCK and GLP-1) are received by target cells. It is based on a new mechanism that acts on the body (CCK receptor or GLP-1 receptor) and exhibits various medicinal effects.
  • the target disease and efficacy of the present invention are based on an increase in C CK concentration in the blood or target organ and an increase in GLP-1 concentration in the blood or target organ.
  • GP C R is activated, and a wide range of treatments with an increase in the concentration of C C K or G L P-1 in the blood or the target organ is possible.
  • therapeutic agents for target diseases associated with increased C C K concentrations For example, the following can be mentioned as therapeutic agents for target diseases associated with increased C C K concentrations.
  • It can be used as a therapeutic agent for diabetes by promoting insulin secretion from spleen i3 cells.
  • the subject of the present invention is not limited to the above, and it can be easily understood that the entire treatment for diseases associated with increased C CK concentration can be the subject.
  • examples of the therapeutic agent for the target disease associated with an increase in the concentration of GLP-1 include the following.
  • Spleen It can be used as an anti-diabetic agent for preventing the transition from hyperglycemia, insulin resistance, obesity, etc. to diabetes by promoting the differentiation and proliferation of 8 cells. Furthermore, it can be used as a medicament for improving the survival rate of transplanted cells at the time of 3 cell transplantation.
  • It can be used as a therapeutic agent for gastric hyperacidity by suppressing gastric acid secretion.
  • It can be used as a therapeutic agent for diarrhea by suppressing intestinal motility.
  • It can be used as an anti-obesity treatment by suppressing appetite.
  • the subject of the present invention is not limited to the above, and it can be easily understood that the entire treatment of the disease associated with the increased concentration of 0-1 can be the subject.
  • the long-chain fatty acid derivative compound of the present invention simultaneously releases CCK and GLP-1 In many cases, both of them exhibit similar efficacy, but they appear to compete with each other in digestive activity. In fact, both cooperate smoothly to perform digestive activity, and the simultaneous release of CCK and GLP-1 is a more physiologically rational therapeutic agent.
  • Nerve cell plasticity nerve transplantation by viability maintenance action, treatment promoting agent at the time of nerve junction or Alzheimer's disease treatment for diseases caused by nerve cell damage,
  • GPR 1 2 0 In addition to the intestinal tract, GPR 1 2 0 is known to occur in the lungs, pituitary gland, fat cells, and tongue. Therefore,
  • the long-chain fatty acid derivative compound of the present invention had an agonistic action on G P R 40 and / or G P R 120.
  • GPR40 is present in knee ⁇ cells, and insulin secretion is promoted by activation of GPPR40. Therefore, the G P R 40 agonist compound is
  • the GPCR agonist containing the long-chain fatty acid derivative compound of the present invention as an active ingredient has the above-mentioned medicinal effects, and can be formulated, for example, as follows.
  • the GPCR agonist of the present invention is formulated to be compatible with a therapeutically appropriate route of administration, including intravenous and oral administration.
  • Solutions or suspensions used for intravenous administration include, but are not limited to, sterile diluents such as water for injection, saline solution, non-volatile oil, polyethylene glycol, glycerin, propylene Lenglycol, or other synthetic solvents, preservatives such as benzyl alcohol or other methylbaraben, anti-oxidants such as ascorbic acid or sodium hydrogen sulfite, soothing agents such as benzalkonium chloride, pro-power-in hydrochloride, A chelating agent such as ethylenediaminetetraacetic acid (EDTA), a buffer such as acetate, citrate, or phosphate, or a drug for osmotic pressure adjustment such as sodium chloride or dextrose. May be included.
  • sterile diluents such as water for injection, saline
  • pH can be adjusted with acids or bases such as hydrochloric acid or sodium hydroxide.
  • Non-diameter preparations are stored in ampoules, glass or plastic disposable syringes or multidose vials.
  • a sterile injectable solution or dispersion medium a sterile aqueous solution (water-soluble) or dispersion medium to prepare at the time of use, and a sterilized powder (freeze-dried). Protein, nucleic acid, etc.).
  • suitable carriers include physiological saline, bacteriostatic water, CR EMO P HOR EL (registered trademark, BASF, Parasippany, NJ), or phosphate buffered saline (PBS ) Is included.
  • PBS phosphate buffered saline
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (such as glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures.
  • a coating agent such as lectin
  • the required particle size is maintained in a dispersion medium, and an appropriate fluidity is maintained by using a surfactant.
  • Various antibacterial and antifungal agents can be used to prevent microbial contamination, such as parabens, chlorobutanol, fenore, asconolevic acid, and thimerosal.
  • compositions that can delay adsorption include agents such as aluminum monostearate and gelatin.
  • Sterile injectable solutions are prepared by adding the required ingredients alone or in combination with the other ingredients, then adding the required amount of the active compound in a suitable solvent and sterilizing.
  • a dispersion medium is prepared by incorporating the active compound into a sterile medium that contains a basic dispersion medium and the other necessary ingredients described above.
  • Sterile powder preparation methods for the preparation of sterile injectable solutions include vacuum drying and lyophilization to prepare a powder containing the active ingredient and any desired ingredients derived from the sterile solution. It is.
  • an inert diluent or a carrier that does not cause harm when taken into the body is included.
  • Oral preparations are, for example, contained in gelatin capsules or compressed into tablets.
  • the active compound is incorporated with excipients and used in the form of tablets, troches, or capsules.
  • Oral preparations can also be prepared using a flowable carrier.
  • pharmaceutically compatible binders, and or adjuvant materials may be included.
  • Tablets, pills, capsules, lozenges and the like may contain any of the following ingredients or compounds with similar properties.
  • Excipients such as microcrystalline cellulose, binders such as arabic gum, tragacanth or gelatin; swelling agents such as starch or lactose, alginic acid, PRI MO GEL, or corn starch; lubricants such as magnesium stearate or STRROTES Agents; lubricants such as colloidal silicon oxide; sweeteners such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylic acid or orange flavor.
  • transmucosal or transdermal administration When a preparation for systemic administration is used, it can be transmucosally or transdermally.
  • penetrants that can penetrate the target barrier are selected.
  • Transmucosal penetrants include surfactants, bile salts, and fusidic acid derivatives.
  • Nasal sprays or suppositories can be used for transmucosal administration.
  • the active compound is formulated in entiments, ointments, jewels or creams.
  • compositions of the invention can also be prepared in the form of suppositories (eg, with bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.
  • suppositories eg, with bases such as cocoa butter and other glycerides
  • retention enemas for rectal delivery.
  • a controlled-release preparation it can be prepared using a carrier that can prevent immediate removal from the body.
  • a carrier that can prevent immediate removal from the body.
  • biodegradable and biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polydalicolic acid, collagen, polyorthoesters, and polylactic acid.
  • Such materials are ALZAC orporation (Mountain V i ew, CA) and NOVA P harmaceutica 1 s, Inc. (Lake Elsinore, CA) and can also be readily prepared by one skilled in the art.
  • Ribosome suspensions can also be used as pharmaceutically acceptable carriers.
  • Useful ribosomes are not limited, but are suitable for use as a lipid composition comprising phosphatidylcholine, cholesterol and PEG-derived phosphatidylethanol (PEG-PE) to be of a size suitable for use.
  • PEG-PE PEG-derived phosphatidylethanol
  • an antibody Fab ′ fragment or the like may be bound to a ribosome via a dysnoden exchange reaction (Martin and Papahadjopoulos, 1 9 8 2). See, for example, the description in E ppstein et al., 1 985; Hwang et al., 1980 for detailed preparation methods.
  • the dose of the GPCR agonist of the present invention depends on the condition of the patient (human) or animal to be administered, the administration method, etc. in the treatment or prevention of a specific disease. It is possible to
  • the dosage level is from about 0.1 ⁇ g kg force to about 2500 mg Zkg per day, more preferably from about 0.5 to about 100 mg Zkg per day.
  • the dosage of the active ingredient for the patient (human) or animal to be treated is between 0.001 and 100 mg mg.
  • the compound is administered on a regimen of 1 to 4 times a day, preferably once or twice a day.
  • the production method of the compound of the present invention is not limited thereto. It can be easily produced by appropriately combining or applying known or known methods.
  • R 2 is a hydrogen atom
  • R 5 CONHR 2 instead of R 5 CONH 2
  • the target compound can be similarly obtained. Obtainable.
  • R ′ is a carboxy protecting group such as a lower alkyl group such as methyl Means a group.
  • Step 1 is a step of producing a compound having the general formula (2), and the compound having the general formula (1) that can be produced by the method described in W0 0 4/1 0 3 9 4 6 This is achieved by subjecting the nitrile compound to the Ritter reaction. This reaction can be carried out in a solvent in the presence or absence of an acid.
  • the solvent is not particularly limited.
  • an acid such as acetic acid or sulfuric acid that uses a reacting nitrile compound can be used.
  • the acid is not particularly limited, but sulfuric acid, hydrochloric acid, acetic acid, trifluoroacetic acid, nitrosonium (NO BF 4 , NOPF 6 ) and the like can be used.
  • the reaction conditions vary depending on the raw materials used, but in general, the reaction is carried out at ⁇ 20 to 100 ° C., preferably 50 to 100 ° C. for 5 minutes to 2 days, preferably 5 hours to 24 hours.
  • a compound having the general formula (2) can be produced.
  • the compound having the general formula (1) can be reacted with an amide compound (R 5 C ONH 2 or R 5 C ONHR 2 ) in a solvent in the presence of a catalyst to have the general formula (2).
  • the production of the compound can be achieved.
  • hafnium (IV) triflate can be used as the catalyst.
  • the solvent is not particularly limited, but ditromethane or the like can be used.
  • reaction conditions vary depending on the raw materials used, but generally 0 to 100 ° C, preferably 5 to 100 ° C for 5 minutes to 2 days, preferably 5 to 24 hours.
  • reaction conditions vary depending on the raw materials used, but generally 0 to 100 ° C, preferably 5 to 100 ° C for 5 minutes to 2 days, preferably 5 to 24 hours.
  • Step 2 is a step of producing a compound having the general formula (3), and is achieved by subjecting the compound having the general formula (2) obtained in [Step 1] to a normal hydrolysis reaction.
  • This reaction, fa can be conducted in the presence of a solvent, base or acid
  • the solvent is not particularly limited, and for example, tetrahydrofuran, dioxane, methanol, ethanol, water and the like can be used alone or in combination.
  • the acid is not particularly limited, but inorganic acids such as sulfuric acid and hydrochloric acid, and organic acids such as acetic acid and trifluoroacetic acid can be used.
  • the base is not particularly limited.
  • lithium hydroxide, sodium hydroxide, metal hydroxides such as lithium hydroxide, lithium carbonate, sodium carbonate, carbonate Umum, cesium carbonate, etc. can be used.
  • reaction conditions vary depending on the raw materials used, but in general, the reaction is carried out at ⁇ 20 to 100 ° C., preferably 15 to 50 ° C. for 5 minutes to 1 day, preferably 30 minutes to 12 hours.
  • the reaction is carried out at ⁇ 20 to 100 ° C., preferably 15 to 50 ° C. for 5 minutes to 1 day, preferably 30 minutes to 12 hours.
  • R 3 is, C, _ 8 alkyl group, the preparation of the compounds is Ararukiru group or the like; hereinafter, although described when R 2 is hydrogen atom, R 2 is the compounds other than hydrogen atom, the step 'R 5 in place of the C ONH 2' in 1 R 5
  • the target compound can be similarly obtained.
  • R ′ means a protecting group for a carboxy group such as a lower alkyl group, such as a methyl group
  • Step 3 is a step of producing a compound having the general formula (4), and subjecting the compound having the general formula (2) obtained in [Step 1] to a selective reduction reaction of an amide group. Is achieved.
  • the reaction can be performed in a solvent in the presence of a catalyst.
  • tetrahydrofuran a dioxane, etc. can be used individually or in combination.
  • Examples of the catalyst include a borane / tetrahydrofuran complex.
  • reaction conditions vary depending on the raw materials used, but in general, the reaction is carried out at ⁇ 20 to 100 ° C., preferably 10 to 25 ° C. for 1 minute to 1 day, preferably 1 hour to 12 hours.
  • To produce a compound having the general formula (4) Can do.
  • Step 4 is a step of producing a compound having the above general formula (5), and the compound having the general formula (4) obtained in [Step 3] is subjected to normal hydrolysis as in the above [Step 2]. This is achieved by reacting.
  • the solvent, base group or acid used in this reaction, and the reaction conditions are the same as those described in [Step 2].
  • R 3 is (wherein, R 4 is - 6 alkyl group means a ⁇ aryl group or Ararukiru group.) In one S_ ⁇ 2 R 4 production of those compounds;
  • R 2 is a hydrogen atom
  • R 4 S 0 2 NHR 2 is used instead of R 4 S 0 2 NH 2 in Step 5
  • the target compound can be obtained in the same manner.
  • R ′ means a protecting group for a carboxy group such as a lower alkyl group, for example, a methyl group
  • R 4 Represents a C- 6 alkyl group, an aryl group or an aralkyl group.
  • Step 5 is a step of producing a compound having the general formula (6). This is achieved by reacting a compound having the general formula (1) with a sulfonamide compound in a solvent in the presence of a catalyst.
  • hafnium (IV) triflate can be used as the catalyst.
  • the solvent is not particularly limited, but ditromethane or the like can be used.
  • reaction conditions vary depending on the raw materials used, but generally 0 to 100 ° C, preferably 5 to 100 ° C for 5 minutes to 2 days, preferably 5 hours to 24 hours.
  • reaction conditions vary depending on the raw materials used, but generally 0 to 100 ° C, preferably 5 to 100 ° C for 5 minutes to 2 days, preferably 5 hours to 24 hours.
  • Step 6 is a step of producing a compound having the above general formula (7), and the compound having the general formula (6) obtained in [Step 5] is subjected to normal hydrolysis in the same manner as in the above [Step 2]. This is achieved by reacting.
  • R ′ means a protecting group for a carboxy group such as a lower alkyl group, such as a methyl group.
  • R 1 represents a hydrogen atom or a C 6 nuisance 6 alkyl group.
  • Step 7 is a step of producing a compound having the general formula (9), and can be produced by a method similar to the method described in the W0 0 4 Z 1 0 3 9 4 6 brochure. It is achieved by reacting a compound having 8) with a hydroxylamine compound or a C, 6 alkyloxyamine compound in a solvent in the presence of a catalyst.
  • sodium acetate, sodium carbonate, ammonia or the like can be used as the catalyst.
  • the solvent is not particularly limited, and for example, tetrahydrofuran, dioxane, methanol, ethanol, water and the like can be used alone or in combination.
  • reaction conditions vary depending on the raw materials used, but generally 0 to 100 ° C, preferably 5 to 100 ° C for 5 minutes to 2 days, preferably 5 hours to 24 hours.
  • reaction conditions vary depending on the raw materials used, but generally 0 to 100 ° C, preferably 5 to 100 ° C for 5 minutes to 2 days, preferably 5 hours to 24 hours.
  • Step 8 is a step for producing a compound having the above general formula (10), and the compound having the general formula (9) obtained in [Step 7] is converted into a conventional hydrolyzate as in the above [Step 2]. This is achieved by a decomposition reaction.
  • the solvent, base or acid used in this reaction, and the reaction conditions are the same as those described in [Step 2].
  • Step 9 is a step of producing a compound having the general formula (11), and is achieved by subjecting the compound having the general formula (1) and an azidating agent to a Mitsunobu reaction.
  • This reaction can be carried out in a solvent in the presence of a phosphine reagent and an azodicarboxylic acid derivative.
  • azide glaze examples include hydrogen azide and diphenyl phosphate azide.
  • phosphine reagent examples include triphenyl phosphine, triethyl phosphine, and the like.
  • azodicarboxylic acid derivative examples include dialkyl esters of azodicarboxylic acid such as jetyl azodicarboxylate or diisopropyl azodicarboxylate, and azodicarboxylic acid amide.
  • the solvent is not particularly limited, and for example, methylene chloride or tetrahydrofuran can be used.
  • reaction conditions vary depending on the raw materials used, but are generally 0 to 100 ° C, preferably 0 to 50 ° C for 5 minutes to 2 days, preferably 1 to 24 hours.
  • reaction conditions vary depending on the raw materials used, but are generally 0 to 100 ° C, preferably 0 to 50 ° C for 5 minutes to 2 days, preferably 1 to 24 hours.
  • Step 10 is a step of producing a compound having the general formula (1 2).
  • the compound having the general formula (1 1) obtained in [Step 9] can be subjected to the usual hydrolysis reaction similar to the above [Step 2] to obtain the carboxylic acid compound of the general formula (1 1). .
  • the solvent, base or acid used in this reaction, and the reaction conditions are [Step
  • the reduction reaction By subjecting the obtained carboxylic acid compound to a reduction reaction, production of the compound of the general formula (12) is achieved.
  • the reduction reaction include catalytic reduction, metal reduction using a hydride-based reducing reagent, and reduction using an organic phosphorus compound.
  • Reductants include palladium-carbon and hydrogen for catalytic reduction, combinations of Raney nickel and hydrogen, and hydride-based reducing reagents such as lithium aluminum hydride, dichloroborane dimethylsulfide complex, and hydrogen.
  • hydride-based reducing reagents such as lithium aluminum hydride, dichloroborane dimethylsulfide complex, and hydrogen.
  • organic phosphorus compound reducing agent such as a combination of sodium borohydride and cobalt chloride is triphenylphosphine.
  • the solvent is not particularly limited, and for example, methanol, ethanol, n-propanol, jetinoreethenole, tetrahydrofuran, dichloromethane, ethyl acetate, water and the like can be used.
  • reaction conditions vary depending on the raw materials used, but are generally 0 to 10 ° C., preferably 0 to 50 ° C. for 5 minutes to 2 days, preferably 1 to 24 hours. It is possible to produce a compound having the general formula (1 2).
  • the present invention will be described in more detail based on examples, but the present invention is not limited to these examples.
  • 12-acetamido-2,2-dichloro-12- (4-chlorophenyl) methinole dodecanoate (40 mg, 0.089 mmol) was dissolved in 1 raL of methanol and 2 mol / L Water A 0.1 mL aqueous lithium oxide solution was added, and the mixture was stirred at room temperature for 1 hour.
  • the target product (yield 100%) was obtained as a colorless oil by using the same method as in Example 1 except that propiononitol was used instead of HN and 0-acetonitol.
  • the target product (yield 34%) was obtained as a colorless oil by using the same method as in Example 1 using isovaleritol instead of acetonitrile.
  • the target product (yield 34%) was obtained as a yellow oil by using cinnamamide instead of benzamide and using the same method as in Example 15.
  • 12- (4-chlorophenyl) -2,2-dichloro-12-cinnamamide dodecanoic acid 45 mg (0.083 mM) in 1 mL methanolate was dissolved in 10% A carbon catalyst was added and stirred at room temperature for 30 minutes in a hydrogen atmosphere.
  • the target product (yield 71%) was obtained as a brown oil by using methanesulfonic acid amide instead of benzamide and using the same method as in Example 15.
  • 2,2-dichloro-12- (4-chlorophenyl) -12-methyl dodecanoate 550 mg, 1.35 mmol
  • Hydroxyamine hydrochloride 103 mg, 1.48 mM
  • sodium acetate 188 mg, 2.29 ra
  • Test 1 Ligand screening of G PR 40 and GP R 120 by extracellular signal-regulated kinase (ERK) Atsey
  • Test 1 The materials and methods used in Test 1 are as follows.
  • T X G P R 4 0 and T X G P R 1 2 0 are the
  • the ligand used is the long chain fatty acid derivative compound according to the present invention.
  • Ligand solution was dripped from above the cell solution, and the dish was gently shaken to diffuse and allowed to react at room temperature.
  • Electrophoresis was performed at a constant current of 40 mA. (Approximately 80 to 90 min)
  • transfer buffer C solution 25raM Tris, 0.02% SDS, 2% methanol, 40 mM 6-aminohexanoic acid
  • Block Ace solution was removed, the primary antibody solution was added, and the reaction was carried out by shaking for 2 hours.
  • the secondary rod (Anti-rabbit Ig, Horseradish Peroxidase linked F (ab) 2 fragment) was diluted 5000 times with TTBS.
  • FIG. 1A shows a test compound using the cell line TXGPR 40. Examples 1 6, 2 1, 2 3, 2 9, 2 7, 2 5. Concentration 10 ⁇ M and 100 ⁇ ⁇ .
  • FIG. 4 is a diagram showing an example of the total ERK detection result using a western blot during stimulation.
  • FIG. 1B shows test compounds using cell line TXGPR 40 (Examples 16, 2, 1, 2, 3, 29, 27, 25, concentrations 10 ⁇ and 100 ⁇ ).
  • FIG. 6 is a diagram showing an example of the detection result of phosphorylated ER ⁇ ⁇ ⁇ by a catalyst.
  • Fig. 1C shows the result of quantifying and graphing the band in Fig. 1 and shows E R ⁇ activity induced by compound stimulation of T XG P R 40.
  • the Phospho ERK / Total E RK values (vertical axis) at the concentrations of 10 and 100 ⁇ of each of the compounds of Examples 16, 6, 21, 2, 3, 29, 27, 25. is there.
  • FIG. 2 is a graph showing the results of GPR 40 screening by ERK assembly using the cell line TXG PR 40 in Test Example 1.
  • the vertical axis represents phospho E RK I total E RK. Normalize with DMS O and PMA and compare values between drugs.
  • the concentration of the test compound is 10 ⁇ M and 100 / i ⁇ .
  • TXCONT without GPCR gene integration and cells not treated with Doxycycline (Dox (-)) are arranged as negative controls and treated with Doxycycline (Dox (+)).
  • ERK activity of the compound Were compared.
  • GPR 40 protein is expressed in cell line TXGPR 40, Examples 4, 6, 8, 1 6, 2 1, 2 3, 2 5, 2 7, 2 9 strongly activated ERK .
  • FIG. 3 is a graph showing the results of comparison of ERK activity of each compound using the cell line T XGPR 120.
  • DM means DMS0 as a negative control
  • PMA means Phorbo 12-myristate-13-acetate as a positive control
  • LA means cis-a-linolenic acid as a positive target.
  • Fig. 3A shows test compounds using cell line TXGPR 120 (with Doxycycline stimulation) (Examples 16, 2, 1, 2, 3, 2, 9, 27, 25, 8. Concentrations of 10 ⁇ M and 100 M.) It is a figure showing an example of the detection result of total ERK by Western blot at the time of stimulation.
  • FIG. 3B shows a test compound using the cell line TXGPR 1 2 0 (Examples 16, 2, 1, 23, 29, 27, 25, 8. Concentrations 10 / x M and 100 M 0 )
  • FIG. 6 is a diagram showing an example of the detection result of phosphorylated ERK by a wet stamp slot during stimulation.
  • FIG. 3C shows the result of numerically graphing the band of FIG. 3B, and shows the ERK activity induced by the compound stimulation of T XG PR 1 20. Specifically, Phospho ER at 10 M and 100 ⁇ M concentrations of Examples 1, 6, 21, 23, 29, 27, 25, 8 K / TotalE RK value (vertical axis).
  • FIG. 4 is a graph showing the results of comparing the ERK activity of each compound using the cell line T XGPR 120. Normalized by DMS O and PMA and compared values between drugs.
  • Dox (+ ) The ERK life of the compounds was compared.
  • the concentration of the test compound is 10 ⁇ M and 100 // ⁇ .
  • GPR 1 2 0 is a cell that possesses GPR 1 2 0 cells as described in papers and patents (Nature Medicine, 11 (1), 90-94, 2005 and JP 2 0 5 — 1 5 3 5 8). Promotes the release of GLP-1 or CCK from the body, coordinated promoter of digestive activity, therapeutic agent of digestive activity disorder; anti-obesity therapeutic agent by appetite suppression, therapeutic agent of bulimia; promotion of differentiation and proliferation of knee cells Diabetes preventive and therapeutic agents, especially therapeutic effect promoters when transplanting ⁇ cells or their progenitor cells; nerve cell plasticity, nerve transplantation by viability maintenance, therapeutic accelerators during nerve junction, or Alzheimer's disease It is effective as a therapeutic agent for intestinal motility during enteritis due to normalization of intestinal motility; a therapeutic agent for lung diseases such as COPD (chronic obstructive pulmonary disease) by promoting surfactant secretion in the lung; Is that It is clear from the following paper.
  • COPD chronic obstructive pulmonary disease
  • Nerve plasticity nerve transplantation by viability maintenance action, treatment promoting agent at the time of nerve junction or treatment for diseases caused by neuronal disorders such as Alzheimer's disease; Curr Drug Target CNS Neurol Disord 2002; 1 (5): 495 -510, Curr Drug Targets. 2004; 5 (69: 565-71, Curr Alzheimer Res 2005, 2 (3): 377-85
  • a therapeutic agent for intestinal motility abnormalities during enteritis due to normalization of intestinal motility
  • Lung disease therapeutic agents such as COPD (chronic obstructive pulmonary disease) by promoting surfactant secretion in the lung;
  • GPR 40 agonist is a therapeutic agent for diseases involving GPR 40, particularly diseases caused by abnormal physiological functions via GPR 40, specifically diabetes caused by promotion of insulin secretion.
  • Therapeutic or preventive agent Knee ⁇ -cell differentiation and proliferation promoter;] Improving the survival rate of transplanted cells at the time of 3-cell transplantation; Preventing the transition from hyperglycemia, insulin resistance, obesity, etc. to diabetes Diabetes preventive agent: Effective as a preventive or therapeutic agent for metabolic syndrome.
  • a compound having agonist activity for GPR 40 and GPR 120 is a disease associated with GPR 40 and / or GPR 120, particularly G GR 40 and ⁇ ⁇ or GPR 120.
  • Therapeutic or prophylactic agent for the above-mentioned diseases caused by abnormal physiological functions for example, antidiabetic agent or prophylactic agent by promoting insulin secretion; spleen] 3-cell differentiation and proliferation promoting agent; hyperglycemia, insulin It is effective as a prophylactic or therapeutic agent for metabolic syndrome, which prevents the transition from resistance and obesity to diabetes.

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Abstract

L'invention concerne un nouveau composé dérivé d'un acide gras à longue chaîne qui présente une activité agonistique envers GPR120 et GPR40. Le composé dérivé d'un acide gras à longue chaîne selon l'invention est représenté par la formule générale (I) suivante. Dans la formule, m + n signifie un entier inférieur ou égal à 20, R représente un atome d'hydrogène ou un résidu d'ester, Y1 et Y2 représentent un atome d'halogène, le cycle Q représente un groupe carbocyclique ou un groupe hétérocyclique qui peut être condensé, X1, X2, et X3 représentent un atome d'hydrogène, un atome d'halogène ou analogue, W représente -C(=N-OR1)-, -CH(NR2R3)- ou -CH(N3)-. Un médicament qui contient le composé dérivé d'un acide gras à longue chaîne en tant qu'ingrédient actif est efficace en tant qu'agent de régulation de l'appétit, agent anti-obésité, agent thérapeutique contre le diabète, accélérateur de la prolifération et de la différenciation des cellules bêta pancréatiques, agent thérapeutique contre le syndrome métabolique, agent thérapeutique contre les maladies gastro-intestinales, agent thérapeutique contre la neuropathie, agent thérapeutique contre les troubles psychiatriques, agent thérapeutique contre les maladies pulmonaires, agent thérapeutique contre la déficience en hormones hypophysaires et assaisonnement de saveur grasse.
PCT/JP2008/067051 2007-09-17 2008-09-16 Nouveau composé dérivé d'un acide gras à longue chaîne et agoniste des récepteurs couplés aux protéines g qui contient le composé en tant qu'ingrédient actif WO2009038204A1 (fr)

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WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
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