Pharmaceutical composition for preventing or treating bone diseases

Abstract

To provide a pharmaceutical composition useful for preventing or treating a bone disease associated with an abnormality in the balance between osteoclasts and osteoblasts, particularly bone diseases accompanied by inflammation, such as periodontal diseases.SOLUTION: The pharmaceutical composition contains a GPR40 agonist and a free fatty acid that is an endogenous ligand of GPR40.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition for preventing or treating bone diseases. The present invention also relates to the use of a GPR40 agonist.

Background Art

[0002] GPR40 (sometimes also referred to as FFAR1 (free fatty acid receptor 1)) is a G protein-coupled receptor that uses free fatty acids as an endogenous ligand and is expressed in pancreatic β-cells, bone-related cells (such as osteoclasts, osteoblasts, and their progenitor cells, etc.). By binding of free fatty acids to GPR40, the activity of the cells expressing the receptor can be regulated. For example, pancreatic β-cells are activated by the binding of free fatty acids to GPR40, and the secretion of insulin is induced.

[0003] On the other hand, various GPR40 agonists (activators), which are compounds other than free fatty acids that can bind to GPR40 and can regulate the activity of GPR40-expressing cells, are also known. For example, Patent Document 1 describes a condensed ring compound represented by a specific structural formula as a GPR40 agonist. In the examples, it is further described that the compound has an activity comparable to that of free fatty acids (γ-linolenic acid) in the secretion of insulin from pancreatic β-cells, and thus may be used for the prevention or treatment of diabetes. Non-Patent Document 1 describes a list of various compounds that become GPR40 agonists.

[0004] Among the condensed ring compounds described in Patent Document 1, there is a compound called Fasiglifam (fasiglifam, development code: TAK-875), [(3S)-6-({2',6'-dimethyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid. Non-Patent Document 2 states that the agonist Fasiglifam binds to a different site (allosteric site) of GPR40 from the free fatty acid which is an endogenous ligand, and when Fasiglifam and the free fatty acid act on GPR at the same time, the secretion of insulin from pancreatic β-cells is enhanced compared to when they act alone.

[0005] In Non-Patent Document 3, the binding modes of linolenic acid, Fasiglifam (TAK-875) and other GPR40 agonists (GW9508, TUG-770, AMG 837, AM 8182, AM 1638) to GPR40 are analyzed by a molecular structure model. Non-Patent Document 4 also details the binding mode of Fasiglifam (TAK-875) to GPR40 by a molecular structure model. Non-Patent Documents 9 and 10 provide reviews of GPR40 agonists, and further examples of GPR40 agonists include TUG-469, AM-5262, LY2881835, etc.

[0006] Also, in Non-Patent Document 5, the individual effects of various free fatty acids and GPR40 / GPR120 agonists (GW9508) on GPR40 expressed in osteoclasts and GPR120 expressed in osteoblasts have been studied, and it has been reported that these free fatty acids and agonists have the effect of suppressing the formation of osteoclasts (differentiation and maturation into osteoclasts) caused by the interaction of osteoclasts (RANK) with osteoblasts (RANKL). Non-Patent Document 6 also describes that through research using the GPR40 / GPR120 agonist (GW9508), the differentiation into osteoclasts is suppressed by the action of GW9508 on GPR40, and thus the bone loss caused by ovariectomy can be prevented.

[0007] In Non-Patent Document 7, it is shown that there is a deep relationship between bone metabolism due to bone resorption and bone destruction and the immune response, and the relevance between the immune response and bone diseases, particularly bone diseases in the oral cavity where inflammation is likely to occur due to bacterial infection, is described. Further, in Non-Patent Document 8, since inflammatory mediators increase and joint destruction worsens in GPR40-deficient animals, it is described that activation of GPR40 may be able to prevent osteoarthritis.

Prior Art Documents

Patent Documents

[0008]

Patent Document 1

Non-Patent Documents

[0009]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Non-Patent Document 7

Non-Patent Document 8

Non-Patent Document 9

Non-Patent Document 10

Summary of the Invention

Problems to be Solved by the Invention

[0010] Osteoclasts, together with osteoblasts and osteocytes, constitute bone, and bone is remodeled (bone remodeling) by bone resorption by osteoclasts and bone formation by osteoblasts. When the balance of the activities of osteoclasts and osteoblasts is disrupted, it causes various bone diseases such as osteoporosis and rheumatoid arthritis.

[0011] In addition, periodontal disease caused by periodontal pathogenic bacteria causes destruction of bone tissue (alveolar bone) along with an increase and chronicization of inflammation in the periodontal tissue, and osteoclasts are also involved in this destruction. However, bisphosphonates, which are used as osteoporosis treatment drugs, induce apoptosis in osteoclasts and increase bone mass by suppressing bone resorption, but in the treatment of periodontal disease, they cause bisphosphonate-related osteonecrosis of the jaw (BRONJ). It has also been reported that osteonecrosis of the jaw occurs in 1 - 2% of cases when using anti-RANKL antibody (denosumab), a next-generation osteoporosis treatment drug that inhibits the function of RANKL, which is essential for the formation and differentiation of osteoclasts. For the prevention or treatment of periodontal disease, it is necessary to suppress the destruction of alveolar bone (jaw bone) in the special environment of the oral cavity where the immune balance is disrupted by bacterial infection and inflammation is likely to occur. Instead of using known osteoporosis treatment drugs as they are, it is required to take new solutions.

[0012] An object of the present invention is to provide a pharmaceutical composition useful for the prevention or treatment of bone diseases related to abnormal balance between osteoclasts and osteoblasts, particularly bone diseases accompanied by inflammation such as periodontal disease.

Means for Solving the Problems

[0013] The inventors have clarified that in the culture system of bone marrow mesenchymal stem cells, the combined use of a GPR40 agonist and a free fatty acid suppresses the differentiation from hematopoietic stem cells to osteoclasts, promotes the differentiation from mesenchymal stem cells to osteoblasts, and changes (increases or decreases) the expression levels of genes highly related to bone metabolism and inflammation. They have also found that these can be excellent active ingredients for pharmaceutical compositions for the prevention or treatment of bone diseases such as periodontal disease.

[0014] That is, the present invention includes the following matters. [Item 1] A pharmaceutical composition for preventing or treating a bone disease, containing a GPR40 agonist and a free fatty acid which is an endogenous ligand of GPR40. [Item 2] The pharmaceutical composition according to Item 1, wherein the GPR40 agonist is a compound represented by formula (I) or a salt thereof, or a prodrug of the compound represented by formula (I). [Chemical formula] [In formula (I), R 1 represents R 6 -SO2-(R 6 represents a substituent.) or an optionally substituted 1,1-dioxidotetrahydropyranyl group; X represents a bond or a divalent hydrocarbon group; R 2 and R 3 each represent a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group or an optionally substituted hydroxy group, and may be the same or different; R 4 and R 5 each represent a C 1-6 alkyl group optionally substituted with a hydroxy group, and may be the same or different; Ring A represents a benzene ring which may further have a substituent selected from the group consisting of a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted hydroxy group and an optionally substituted amino group; Ring B represents a 5- to 7-membered ring; Y represents a bond or CH2; R represents an optionally substituted hydroxy group.] [Item 3]<^ The pharmaceutical composition according to Item 1, wherein the free fatty acid that is an endogenous ligand of GPR40 is one or more saturated or unsaturated fatty acids having 6 to 22 carbon atoms. [Item 4] The pharmaceutical composition according to Item 1, wherein the bone disease is a bone disease accompanied by inflammation. [Item 5] The pharmaceutical composition according to Item 4, wherein the bone disease accompanied by inflammation is a disease, symptom or condition accompanied by alveolar bone resorption in periodontal disease, alveolar bone resorption after tooth extraction, bone resorption after alveolar bone augmentation surgery or other alveolar bone resorption. [Item 6] The pharmaceutical composition according to Item 1, wherein the bone disease is a refractory / rare disease having a bone symptom or a pathological condition of a tissue related to bone or a pathological condition of blood cells in bone or a tissue related to bone. [Item 7] A method for preventing or treating a bone disease in a mammal, comprising administering to the mammal an effective amount of a GPR40 agonist and an effective amount of a free fatty acid that is an endogenous ligand of GPR40. [Item 8] Use of a GPR40 agonist and a free fatty acid that is an endogenous ligand of GPR40 for producing a pharmaceutical composition for preventing or treating a bone disease. [Advantages of the Invention]

[0015] The present invention provides pharmaceutical compositions for bone diseases that are more effective in preventing or treating bone diseases than conventional pharmaceutical compositions. For example, even if a GPR40 agonist alone or a free fatty acid (a GPR40 ligand) alone does not sufficiently inhibit osteoclast differentiation, the combined use of a GPR40 agonist and a free fatty acid may achieve sufficient effects. Furthermore, the expression levels of some genes closely related to bone metabolism and inflammation are not altered by the use of a GPR40 agonist alone or a free fatty acid (a GPR40 ligand) alone, but are altered by the use of a GPR40 agonist and a free fatty acid together. Therefore, the combination of the above two components can be said to have a significant effect as an active ingredient in a pharmaceutical composition for preventing or treating bone diseases, particularly bone diseases accompanied by inflammation such as periodontal disease. The pharmaceutical composition of the present invention containing the above two components enables effective prevention or treatment of alveolar bone loss due to periodontal disease, which has been difficult to achieve until now. [Brief explanation of the drawings]

[0016]

Figure 1

Figure 2

Figure 3

[0017] -Pharmaceutical composition- The pharmaceutical composition of the present invention contains a GPR40 agonist as a first component and a free fatty acid that is an endogenous ligand of GPR40 as a second component, and is used for the prevention or treatment of bone diseases.

[0018] · Component 1: GPR40 agonist Various compounds are known as "GPR40 agonists". For example, the compounds described in the aforementioned Patent Document 1, the compounds described in WO2004 / 041266, WO2004 / 106276, WO2005 / 063729 shown in its background art, and GW9508, TUG-770, TUG-469, AMG 837, AM 8182, AM 1638, AM-5262, LY2881835 described in the aforementioned Non-Patent Documents 3, 9, and 10 are cited as "GPR40 agonists". The list described in the aforementioned Non-Patent Document 1 can also be referred to. The "GPR40 agonist" that can be used as Component 1 of the pharmaceutical composition of the present invention is not particularly limited and can be selected in consideration of the effects of the present invention. Any one kind of GPR40 agonist may be used alone, or two or more kinds may be used in combination.

[0019] Among GPR40 agonists, there are those that bind to the same site (orthosteric site) as free fatty acids in GPR40 and those that bind to a site different from free fatty acids (allosteric site). However, the GPR40 agonist used in the present invention is preferably the latter.

[0020] In addition, medium-chain or long-chain free fatty acids, which are endogenous ligands of GPR40, are also endogenous ligands of GPR120 (FFAR4) in addition to GPR40. The GPR40 agonist used in the present invention may be a non-selective agonist (dual agonist) that also acts as an agonist of GPR120 (acts as an agonist of both GPR40 and GPR120), or a selective agonist that does not act as an agonist of GPR120 (acts only as an agonist of GPR40). For example, Fasiglifam (TAK-875) is a selective agonist for GPR40, and GW9508 is a dual agonist for GPR40 and GPR120.

[0021] In a preferred embodiment of the present invention, the GPR40 agonist used as the first component of the pharmaceutical composition of the present invention is a compound represented by the formula (I) (referred to herein as "compound (I)") or a salt thereof, or a prodrug of compound (I), as described in the aforementioned Patent Document 1. Fasiglifam (TAK-875) is a representative example of compound (I) and is a compound suitable as a selective agonist of GPR40.

[0022]

Chemical formula

[0023] In formula (I), R 1 represents R 6 -SO2-(R 6 represents a substituent.) or an optionally substituted 1,1-dioxidotetrahydrothiopyranyl group; X represents a bond or a divalent hydrocarbon group; R 2 and R 3 each represent a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group or an optionally substituted hydroxy group, and may be the same or different; R 4 and R 5 each represent a C 1-6 alkyl group optionally substituted with a hydroxy group, and may be the same or different; Ring A represents a benzene ring which may further have a substituent selected from the group consisting of a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted hydroxy group and an optionally substituted amino group; Ring B represents a 5- to 7-membered ring; Y represents a bond or CH2; R represents an optionally substituted hydroxy group.

[0024] Unless otherwise specified, the "halogen atom" in this specification includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

[0025] As used herein, the "optionally substituted hydrocarbon group" includes, unless otherwise specified, for example, "optionally substituted C 1-6 alkyl group", "optionally substituted C 2-6 alkenyl group", "optionally substituted C 2-6 alkynyl group", "optionally substituted C 3-8 cycloalkyl group", "optionally substituted C 6-14 aryl group", "optionally substituted C 7-16 aralkyl group", and the like.

[0026] As used herein, the "C 1-6 alkyl group" includes, unless otherwise specified, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, and the like.

[0027] As used herein, the "C 2-6 alkenyl group" includes, unless otherwise specified, for example, vinyl, propenyl, isopropenyl, 2-buten-1-yl, 4-penten-1-yl, 5-hexen-1-yl, and the like.

[0028] As used herein, the "C 2-6 alkynyl group" includes, unless otherwise specified, for example, 2-butyn-1-yl, 4-pentyn-1-yl, 5-hexyn-1-yl, and the like.

[0029] As used herein, the "C 3-8 cycloalkyl group" includes, unless otherwise specified, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0030] As used herein, the "C 6-14 aryl group" includes, unless otherwise specified, for example, phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl, and the like. The C6-14 Aryl may be partially saturated, and the partially saturated C 6-14 Examples of aryl include tetrahydronaphthyl and the like.

[0031] In this specification, "C 7-16 Unless otherwise specified, examples of the "aralkyl group" in this specification include benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 2-biphenylylmethyl, 3-biphenylylmethyl, 4-biphenylylmethyl, and the like.

[0032] Unless otherwise specified, examples of the "optionally substituted hydroxy group" in this specification include, for example, "hydroxy group", "optionally substituted C 1-6 alkoxy group", "optionally substituted heterocyclic oxy group", "optionally substituted C 6-14 aryloxy group", "optionally substituted C 7-16 aralkyloxy group", and the like.

[0033] In this specification, "C 1-6 Unless otherwise specified, examples of the "alkoxy group" in this specification include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, and the like.

[0034] In this specification, "C 1-6 alkoxy-C 1-6 Unless otherwise specified, examples of the "alkoxy-alkoxy group" in this specification include methoxymethoxy, methoxyethoxy, ethoxymethoxy, ethoxyethoxy, and the like.

[0035] As used herein, the "heterocyclic oxy group" includes a hydroxy group substituted with a "heterocyclic group" described below. Preferred examples of the heterocyclic oxy group include tetrahydropyranyloxy, thiazolyloxy, pyridyloxy, pyrazolyloxy, oxazolyloxy, thienyloxy, furyloxy and the like.

[0036] As used herein, the "C 6-14 aryloxy group" includes, unless otherwise specified, for example, phenoxy, 1-naphthyloxy, 2-naphthyloxy and the like.

[0037] As used herein, the "C 7-16 aralkyloxy group" includes, unless otherwise specified, for example, benzyloxy, phenethyloxy and the like.

[0038] As used herein, the "optionally substituted mercapto group" includes, unless otherwise specified, for example, "mercapto group", "optionally substituted C 1-6 alkylthio group", "optionally substituted heterocyclic thio group", "optionally substituted C 6-14 arylthio group", "optionally substituted C 7-16 aralkylthio group" and the like.

[0039] As used herein, the "C 1-6 alkylthio group" includes, unless otherwise specified, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio and the like.

[0040] As used herein, the "heterocyclic thio group" includes a mercapto group substituted with a "heterocyclic group" described below. Preferred examples of the heterocyclic thio group include tetrahydropyranylthio, thiazolylthio, pyridylthio, pyrazolylthio, oxazolylthio, thienylthio, furylthio and the like.

[0041] As used herein, the "C 6-14The "arylthio group" includes, unless otherwise specified, for example, phenylthio, 1-naphthylthio, 2-naphthylthio and the like.

[0042] The "C 7-16 The "aralkylthio group" includes, unless otherwise specified, for example, benzylthio, phenethylthio and the like.

[0043] As used herein, the "heterocyclic group" refers to, unless otherwise specified, for example, a 5- to 14-membered (monocyclic, bicyclic or tricyclic) heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms as ring-constituting atoms, 1 to 4 heteroatoms, preferably (i) a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic group, (ii) a 5- to 10-membered non-aromatic heterocyclic group, etc. Among them, a 5- or 6-membered aromatic heterocyclic group is preferred. Specifically, for example, thienyl (e.g., 2-thienyl, 3-thienyl), furyl (e.g., 2-furyl, 3-furyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrazinyl, pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (e.g., 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), triazolyl (e.g., 1-triazolyl, 2-triazolyl), tetrazolyl, pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl), isothiazolyl (e.g., 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), indolyl (e.g., 1-indolyl, 2-indolyl, 3-indolyl), 2-benzothiazolyl, 2-benzoxazolyl, benzimidazolyl (e.g., 1-benzimidazolyl, 2-benzimidazolyl), benzo[b]thienyl (e.g., 2-benzo[b]thienyl, 3-benzo[b]thienyl), benzo[b]furanyl (e.g., 2-benzo[b]furanyl, 3-benzo[b]furanyl), quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl), etc. aromatic heterocyclic groups; For example, non-aromatic heterocyclic groups such as pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl), oxazolidinyl (e.g., 2-oxazolidinyl), imidazolinyl (e.g., 1-imidazolinyl, 2-imidazolinyl, 4-imidazolinyl), piperidinyl (e.g., piperidino, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl), piperazinyl (e.g., 1-piperazinyl, 2-piperazinyl), morpholinyl (e.g., 2-morpholinyl, 3-morpholinyl, morpholino), thiomorpholinyl (e.g., 2-thiomorpholinyl, 3-thiomorpholinyl, thiomorpholino), tetrahydropyranyl, etc. can be mentioned.

[0044] The "C 1-6 alkyl-carbonyl group" in this specification, unless otherwise specified, includes, for example, acetyl, isobutanoyl, isopentanoyl, etc.

[0045] The "C 1-6 alkoxy-carbonyl group" in this specification, unless otherwise specified, includes, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, etc.

[0046] The "C 3-8 cycloalkyl-carbonyl group" in this specification, unless otherwise specified, includes, for example, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.

[0047] The "C 6-14 aryl-carbonyl group" in this specification, unless otherwise specified, includes, for example, benzoyl, 1-naphthoyl, 2-naphthoyl, etc.

[0048] The "C 7-16 aralkyl-carbonyl group" in this specification, unless otherwise specified, includes, for example, phenylacetyl, 2-phenylpropanoyl, etc.

[0049] The "C 6-14The "aryl-oxy-carbonyl group" includes, for example, phenoxycarbonyl, naphthyloxycarbonyl, etc., unless otherwise specified.

[0050] The "C 7-16 The "aralkyloxy-carbonyl group" includes, for example, benzyloxycarbonyl, phenethyloxycarbonyl, etc., unless otherwise specified.

[0051] The "nitrogen-containing heterocyclic-carbonyl group" includes, for example, pyrrolidinylcarbonyl, piperidinocarbonyl, etc., unless otherwise specified.

[0052] The "C 1-6 The "alkylsulfonyl group" includes, for example, methylsulfonyl, ethylsulfonyl, etc., unless otherwise specified.

[0053] The "C 6-14 The "arylsulfonyl group" includes, for example, phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl, etc., unless otherwise specified.

[0054] The "C 1-6 The "alkylsulfinyl group" includes, for example, methylsulfinyl, ethylsulfinyl, etc., unless otherwise specified.

[0055] The "C 6-14 The "arylsulfinyl group" includes, for example, phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl, etc., unless otherwise specified.

[0056] The "optionally esterified carboxyl group" includes, for example, carboxyl, C 1-6 alkoxy-carbonyl group, C 6-14 aryloxy-carbonyl group, C 7-16 aralkyloxy-carbonyl group, etc.

[0057] In this specification, the "optionally halogenated C 1-6 alkyl group" refers to, unless otherwise specified, the above-mentioned "C 1-6 alkyl group" which may be substituted with 1 to 5 of the above-mentioned "halogen atoms". Examples include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, trifluoromethyl, and the like.

[0058] In this specification, the "optionally halogenated C 1-6 alkoxy group" refers to, unless otherwise specified, the above-mentioned "C 1-6 alkoxy group" which may be substituted with 1 to 5 of the above-mentioned "halogen atoms". Examples include methoxy, ethoxy, isopropoxy, tert-butoxy, trifluoromethoxy, and the like.

[0059] In this specification, the "mono- or di-C 1-6 alkyl-amino group" refers to, unless otherwise specified, an amino group mono- or di-substituted with the above-mentioned "C 1-6 alkyl group". Examples include methylamino, ethylamino, propylamino, dimethylamino, diethylamino, and the like.

[0060] In this specification, the "mono- or di-C 6-14 aryl-amino group" refers to, unless otherwise specified, an amino group mono- or di-substituted with the above-mentioned "C 6-14 aryl group". Examples include phenylamino, diphenylamino, 1-naphthylamino, 2-naphthylamino, and the like.

[0061] In this specification, the "mono- or di-C 7-16 aralkyl-amino group" refers to, unless otherwise specified, an amino group mono- or di-substituted with the above-mentioned "C 7-16 aralkyl group". Examples include benzylamino, phenethylamino, and the like.

[0062] As used herein, the term "N-C 1-6 alkyl-N-C 6-14 aryl-amino group" refers to an amino group substituted with the above-mentioned "C 1-6 alkyl group" and the above-mentioned "C 6-14 aryl group", unless otherwise specified. Examples thereof include N-methyl-N-phenylamino, N-ethyl-N-phenylamino and the like.

[0063] As used herein, the term "N-C 1-6 alkyl-N-C 7-16 aralkyl-amino group" refers to an amino group substituted with the above-mentioned "C 1-6 alkyl group" and the above-mentioned "C 7-16 aralkyl group", unless otherwise specified. Examples thereof include N-methyl-N-benzylamino, N-ethyl-N-benzylamino and the like.

[0064] As used herein, the term "mono- or di-C 1-6 alkyl-carbamoyl group" refers to a carbamoyl group mono- or di-substituted with the above-mentioned "C 1-6 alkyl group", unless otherwise specified. Examples thereof include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl and the like.

[0065] As used herein, the term "mono- or di-C 6-14 aryl-carbamoyl group" refers to a carbamoyl group mono- or di-substituted with the above-mentioned "C 6-14 aryl group", unless otherwise specified. Examples thereof include phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl and the like.

[0066] As used herein, the term "mono- or di-C 3-8 cycloalkyl-carbamoyl group" refers to a carbamoyl group mono- or di-substituted with the above-mentioned "C 3-8 cycloalkyl group", unless otherwise specified. Examples thereof include cyclopropylcarbamoyl and the like.

[0067] As used herein, the term "mono- or di-C 7-16 aralkyl-carbamoyl group" refers to, unless otherwise specified, a carbamoyl group mono- or di-substituted with the above-mentioned "C 7-16 aralkyl group". Examples thereof include benzylcarbamoyl.

[0068] As used herein, the term "mono- or di-5- to 7-membered heterocyclic-carbamoyl group" refers to, unless otherwise specified, a carbamoyl group mono- or di-substituted with a 5- to 7-membered heterocyclic group. Herein, examples of the 5- to 7-membered heterocyclic group include a heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen, sulfur, and oxygen atoms in addition to carbon atoms as ring-constituting atoms, and 1 to 4 heteroatoms. Preferable examples of the "mono- or di-5- to 7-membered heterocyclic-carbamoyl group" include 2-pyridylcarbamoyl, 3-pyridylcarbamoyl, 4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl, and the like.

[0069] As used herein, the term "mono- or di-C 1-6 alkyl-sulfamoyl group" refers to, unless otherwise specified, a sulfamoyl group mono- or di-substituted with the above-mentioned "C 1-6 alkyl group". Examples thereof include methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl, and the like.

[0070] As used herein, the term "mono- or di-C 6-14 aryl-sulfamoyl group" refers to, unless otherwise specified, a sulfamoyl group mono- or di-substituted with the above-mentioned "C 6-14 aryl group". Examples thereof include phenylsulfamoyl, diphenylsulfamoyl, 1-naphthylsulfamoyl, 2-naphthylsulfamoyl, and the like.

[0071] As used herein, the term "mono- or di-C 7-16 aralkyl-sulfamoyl group" refers to, unless otherwise specified, a sulfamoyl group mono- or di-substituted with the above-mentioned "C7-16 Examples of the sulfamoyl group mono- or di-substituted with an "aralkyl group" include benzylsulfamoyl.

[0072] The "optionally substituted C 1-6 alkyl group", "optionally substituted C 2-6 alkenyl group", "optionally substituted C 2-6 alkynyl group", "optionally substituted C 1-6 alkoxy group" and "optionally substituted C 1-6 alkylthio group" include, for example, (1) a halogen atom; (2) a hydroxy group; (3) an amino group; (4) a nitro group; (5) a cyano group; (6) a halogen atom, a hydroxy group, an amino group, a nitro group, a cyano group, an optionally halogenated C 1-6 alkyl group, a mono- or di-C 1-6 alkyl-amino group, a C 6-14 aryl group, a mono- or di-C 6-14 aryl-amino group, a C 3-8 cycloalkyl group, a C 1-6 alkoxy group, a C 1-6 alkoxy-C 1-6 alkoxy group, a C 1-6 alkylthio group, a C 1-6 alkylsulfinyl group, an optionally esterified carboxyl group, a carbamoyl group, a thiocarbamoyl group, a mono- or di-C 1-6 alkyl-carbamoyl group, a mono- or di-C 1-6 aryl-carbamoyl group, a sulfamoyl group, a mono- or di-C 6-14 alkyl-sulfamoyl group and a mono- or di-C 1-6 aryl-sulfamoyl group, and a heterocyclic group (preferably furyl, pyridyl, thienyl, pyrazolyl, thiazolyl, oxazolyl) optionally substituted with 1 to 3 substituents selected from 6-14 a mono- or di-C (7) a mono- or di-C1-6 Alkyl - amino group; (8) Mono - or di - C 6-14 Aryl - amino group; (9) Mono - or di - C 7-16 Aralkyl - amino group; (10) N - C 1-6 Alkyl - N - C 6-14 Aryl - amino group; (11) N - C 1-6 Alkyl - N - C 7-16 Aralkyl - amino group; (12) C 3-8 Cycloalkyl group; (13) Optionally halogenated C 1-6 Alkoxy group; (14) C 1-6 Alkylthio group; (15) C 1-6 Alkylsulfinyl group; (16) C 1-6 Alkylsulfonyl group; (17) Optionally esterified carboxyl group; (18) C 1-6 Alkyl - carbonyl group; (19) C 3-8 Cycloalkyl - carbonyl group; (20) C 6-14 Aryl - carbonyl group; (21) Carbamoyl group; (22) Thiocarbamoyl group; (23) Mono - or di - C 1-6 Alkyl - carbamoyl group; (24) Mono - or di - C 6-14 Aryl - carbamoyl group; (25) Mono - or di - 5 - to 7 - membered heterocyclic - carbamoyl group; (26) Optionally substituted with a carboxyl group C 1-6 Alkyl - carbonylamino group (e.g., acetylamino, propionylamino); (27) Halogen atom, hydroxy group, amino group, nitro group, cyano group, optionally halogenated C 1-6 Alkyl group, mono - or di - C1-6 an alkyl - amino group, C 6-14 an aryl group, mono - or di - C 6-14 an aryl - amino group, C 3-8 a cycloalkyl group, C 1-6 an alkoxy group, C 1-6 alkoxy - C 1-6 an alkoxy group, C 1-6 an alkylthio group, C 1-6 an alkylsulfinyl group, C 1-6 an alkylsulfonyl group, a carboxyl group which may be esterified, a carbamoyl group, a thiocarbamoyl group, mono - or di - C 1-6 an alkyl - carbamoyl group, mono - or di - C 6-14 an aryl - carbamoyl group, a sulfamoyl group, mono - or di - C 1-6 an alkyl - sulfamoyl group and mono - or di - C 6-14 an aryl - sulfamoyl group, and may be substituted with 1 to 3 substituents selected from C 6-14 an aryloxy group; (28) a halogen atom, a hydroxy group, an amino group, a nitro group, a cyano group, a C which may be halogenated 1-6 an alkyl group, mono - or di - C 1-6 an alkyl - amino group, C 6-14 an aryl group, mono - or di - C 6-14 an aryl - amino group, C 3-8 a cycloalkyl group, C 1-6 an alkoxy group, C 1-6 alkoxy - C 1-6 an alkoxy group, C 1-6 an alkylthio group, C 1-6 an alkylsulfinyl group, C 1-6 an alkylsulfonyl group, a carboxyl group which may be esterified, a carbamoyl group, a thiocarbamoyl group, mono - or di - C 1-6 an alkyl - carbamoyl group, mono - or di - C 6-14 an aryl - carbamoyl group, a sulfamoyl group, mono - or di - C 1-6 an alkyl - sulfamoyl group and mono - or di - C 6-14 an aryl - sulfamoyl group, and may be substituted with 1 to 3 substituents selected from C6-14 Aryl group; (29) Heterocyclic oxy group; (30) Sulfamoyl group; (31) Mono- or di-C 1-6 Alkyl-sulfamoyl group; (32) Mono- or di-C 6-14 Aryl-sulfamoyl group; (33) Halogen atom, hydroxy group, amino group, nitro group, cyano group, optionally halogenated C 1-6 Alkyl group, mono- or di-C 1-6 Alkyl-amino group, C 6-14 Aryl group, mono- or di-C 6-14 Aryl-amino group, C 3-8 Cycloalkyl group, C 1-6 Alkoxy group, C 1-6 Alkoxy-C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Alkylsulfinyl group, C 1-6 Alkylsulfonyl group, optionally esterified carboxyl group, carbamoyl group, thiocarbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group, mono- or di-C 6-14 Aryl-carbamoyl group, sulfamoyl group, mono- or di-C 1-6 Alkyl-sulfamoyl group and mono- or di-C 6-14 Aryl-sulfamoyl group, optionally substituted with 1 to 3 substituents selected from 7-16 Aralkyl-oxy group; etc., optionally having 1 to 5 substituents selected from each at substitutable positions, "C 1-6 Alkyl group", "C 2-6 Alkenyl group", "C 2-6 Alkynyl group", "C 1-6 Alkoxy group" and "C 1-6 Alkylthio group".

[0073] In this specification, "optionally substituted C 3-8 Cycloalkyl group", "optionally substituted C6-14 "aryl group", "optionally substituted C 7-16 "aralkyl group", "optionally substituted heterocyclic group", "optionally substituted heterocyclic oxy group", "optionally substituted C 6-14 "aryloxy group", "optionally substituted C 7-16 "aralkyloxy group", "optionally substituted heterocyclic thio group", "optionally substituted C 6-14 "arylthio group" and "optionally substituted C 7-16 "aralkylthio group" include, for example, (1) a halogen atom; (2) a hydroxy group; (3) an amino group; (4) a nitro group; (5) a cyano group; (6) optionally substituted C 1-6 "alkyl group"; (7) optionally substituted C 2-6 "alkenyl group"; (8) optionally substituted C 2-6 "alkynyl group"; (9) a halogen atom, a hydroxy group, an amino group, a nitro group, a cyano group, optionally halogenated C 1-6 "alkyl group", mono- or di-C 1-6 "alkyl-amino group", C 6-14 "aryl group", mono- or di-C 6-14 "aryl-amino group", C 3-8 "cycloalkyl group", C 1-6 "alkoxy group", C 1-6 "alkoxy-C 1-6 "alkoxy group", C 1-6 "alkylthio group", C 1-6 "alkylsulfinyl group", C 1-6 "alkylsulfonyl group, optionally esterified carboxyl group, carbamoyl group, thiocarbamoyl group, mono- or di-C 1-6 "alkyl-carbamoyl group", mono- or di-C 6-14 "aryl-carbamoyl group", sulfamoyl group, mono- or di-C 1-6 "alkyl-sulfamoyl group and mono- or di-C 6-14A C optionally substituted with 1 to 3 substituents selected from aryl-sulfamoyl groups 6-14 aryl group; (10) A halogen atom, a hydroxy group, an amino group, a nitro group, a cyano group, a C optionally halogenated 1-6 alkyl group, mono- or di-C 1-6 alkyl-amino group, C 6-14 aryl group, mono- or di-C 6-14 aryl-amino group, C 3-8 cycloalkyl group, C 1-6 alkoxy group, C 1-6 alkoxy-C 1-6 alkoxy group, C 1-6 alkylthio group, C 1-6 alkylsulfinyl group, C 1-6 alkylsulfonyl group, a carboxyl group optionally esterified, a carbamoyl group, a thiocarbamoyl group, mono- or di-C 1-6 alkyl-carbamoyl group, mono- or di-C 6-14 aryl-carbamoyl group, sulfamoyl group, mono- or di-C 1-6 alkyl-sulfamoyl group and mono- or di-C 6-14 A C optionally substituted with 1 to 3 substituents selected from aryl-sulfamoyl groups 6-14 aryloxy group; (11) A halogen atom, a hydroxy group, an amino group, a nitro group, a cyano group, a C optionally halogenated 1-6 alkyl group, mono- or di-C 1-6 alkyl-amino group, C 6-14 aryl group, mono- or di-C 6-14 aryl-amino group, C 3-8 cycloalkyl group, C 1-6 alkoxy group, C 1-6 alkoxy-C 1-6 alkoxy group, C 1-6 alkylthio group, C 1-6 alkylsulfinyl group, C 1-6 alkylsulfonyl group, a carboxyl group optionally esterified, a carbamoyl group, a thiocarbamoyl group, mono- or di-C 1-6An alkyl-carbamoyl group, mono- or di-C 6-14 An aryl-carbamoyl group, a sulfamoyl group, mono- or di-C 1-6 An alkyl-sulfamoyl group and mono- or di-C 6-14 An aryl-sulfamoyl group, which may be substituted with 1 to 3 substituents selected from the group consisting of C 7-16 An aralkyl-oxy group; (12) A halogen atom, a hydroxy group, an amino group, a nitro group, a cyano group, a C which may be halogenated 1-6 An alkyl group, mono- or di-C 1-6 An alkyl-amino group, C 6-14 An aryl group, mono- or di-C 6-14 An aryl-amino group, C 3-8 A cycloalkyl group, C 1-6 An alkoxy group, C 1-6 An alkoxy-C 1-6 An alkoxy group, C 1-6 An alkylthio group, C 1-6 An alkylsulfinyl group, C 1-6 An alkylsulfonyl group, a carboxyl group which may be esterified, a carbamoyl group, a thiocarbamoyl group, mono- or di-C 1-6 An alkyl-carbamoyl group, mono- or di-C 6-14 An aryl-carbamoyl group, a sulfamoyl group, mono- or di-C 1-6 An alkyl-sulfamoyl group and mono- or di-C 6-14 A heterocyclic group (preferably furyl, pyridyl, thienyl, pyrazolyl, thiazolyl, oxazolyl) which may be substituted with 1 to 3 substituents selected from the group consisting of an aryl-sulfamoyl group; (13) Mono- or di-C 1-6 An alkyl-amino group; (14) Mono- or di-C 6-14 An aryl-amino group; (15) Mono- or di-C 7-16 An aralkyl-amino group; (16) N-C 1-6 An alkyl-N-C 6-14 An aryl-amino group; (17) N-C 1-6Alkyl-N-C 7-16 Aralkyl - amino group; (18)C 3-8 Cycloalkyl group; (19)Optionally substituted C 1-6 Alkoxy group; (20)Optionally substituted C 1-6 Alkylthio group; (21)C 1-6 Alkylsulfinyl group; (22)C 1-6 Alkylsulfonyl group; (23)Optionally esterified carboxyl group; (24)C 1-6 Alkyl - carbonyl group; (25)C 3-8 Cycloalkyl - carbonyl group; (26)C 6-14 Aryl - carbonyl group; (27)Carbamoyl group; (28)Thiocarbamoyl group; (29)Mono - or di - C 1-6 Alkyl - carbamoyl group; (30)Mono - or di - C 6-14 Aryl - carbamoyl group; (31)Mono - or di - 5 - to 7 - membered heterocyclic - carbamoyl group; (32)Sulfamoyl group; (33)Mono - or di - C 1-6 Alkyl - sulfamoyl group; (34)Mono - or di - C 6-14 Aryl - sulfamoyl group; (35)Optionally substituted by carboxyl group C 1-6 Alkyl - carbonylamino group (e.g., acetylamino, propionylamino); (36)Heterocyclic oxy group; etc., may each have 1 to 5 substituents selected from the substitutable positions, "C 3-8 Cycloalkyl group", "C 6-14 Aryl group", "C 7-16"aralkyl group", "heterocyclic group", "heterocyclic oxy group", "C" 6-14 "aryloxy group", "C" 7-16 "aralkyloxy group", "heterocyclic thio group", "C" 6-14 "arylthio group" and "C" 7-16 "aralkylthio group" may be mentioned.

[0074] The "optionally substituted amino group" in this specification, unless otherwise specified, (1) Optionally substituted C 1-6 alkyl group; (2) Optionally substituted C 2-6 alkenyl group; (3) Optionally substituted C 2-6 alkynyl group; (4) Optionally substituted C 3-8 cycloalkyl group; (5) Optionally substituted C 6-14 aryl group; (6) Optionally substituted C 1-6 alkoxy group; (7) Optionally substituted acyl group; (8) Optionally substituted heterocyclic group (preferably furyl, pyridyl, thienyl, pyrazolyl, thiazolyl, oxazolyl); (9) Sulfamoyl group; (10) Mono- or di-C 1-6 alkyl-sulfamoyl group; (11) Mono- or di-C 6-14 aryl-sulfamoyl group; Examples of the amino group which may be substituted with one or two substituents selected from the like include. When the "optionally substituted amino group" is an amino group substituted with two substituents, these substituents may form a nitrogen-containing heterocyclic ring together with the adjacent nitrogen atom. Examples of the "nitrogen-containing heterocyclic ring" include 5- to 7-membered nitrogen-containing heterocyclic rings which contain at least one nitrogen atom other than carbon atoms as ring-constituting atoms and may further contain one or two heteroatoms selected from oxygen atoms, sulfur atoms and nitrogen atoms. Preferable examples of the nitrogen-containing heterocyclic ring include pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine, thiazolidine, oxazolidine and the like.

[0075] The "optionally substituted acyl group" in the present specification, unless otherwise specified, refers to a group represented by the formula: -COR7, -CO-OR7, -SO2R7, -SOR7, -PO(OR7)(OR8), -CO-NR 7a R 8a and -CS-NR 7a R 8a [wherein, R7 and R8 are the same or different and each represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and R 7a and R 8a are the same or different and each represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, or R 7a and R 8a may form an optionally substituted nitrogen-containing heterocyclic ring together with the adjacent nitrogen atom] and the like.

[0076] R 7a and R 8aThe "nitrogen-containing heterocyclic ring" in the "optionally substituted nitrogen-containing heterocyclic ring" formed together with an adjacent nitrogen atom includes, for example, a 5- to 7-membered nitrogen-containing heterocyclic ring containing at least 1 nitrogen atom other than a carbon atom as a ring-constituting atom and optionally containing 1 or 2 heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom. Preferable examples of the nitrogen-containing heterocyclic ring include pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine, thiazolidine, oxazolidine, and the like.

[0077] The nitrogen-containing heterocyclic ring may have 1 or 2 substituents at substitutable positions. Such substituents include a hydroxy group, an optionally halogenated C 1-6 alkyl group, a C 6-14 aryl group, a C 7-16 aralkyl group, and the like.

[0078] Preferable examples of the "optionally substituted acyl group" include a formyl group; a carboxyl group; ]>a carbamoyl group; a C 1-6 alkyl-carbonyl group; a C 1-6 alkoxy-carbonyl group; a C 3-8 cycloalkyl-carbonyl group; a C 6-14 aryl-carbonyl group; a C 7-16 aralkyl-carbonyl group; a C 6-14 aryloxy-carbonyl group; a C 7-16 aralkyloxy-carbonyl group; a mono- or di-C 1-6 alkyl-carbamoyl group; a mono- or di-C 6-14 aryl-carbamoyl group; a mono- or di-C 3-8 cycloalkyl-carbamoyl group; a mono- or di-C7-16 Aralkyl-carbamoyl group; C 1-6 Alkylsulfonyl group; C which may be substituted with a nitro group 6-14 Arylsulfonyl group; Nitrogen-containing heterocyclic-carbonyl group; C 1-6 Alkylsulfinyl group; C 6-14 Arylsulfinyl group; Thiocarbamoyl group; Sulfamoyl group; Mono- or di-C 1-6 Alkyl-sulfamoyl group; Mono- or di-C 6-14 Aryl-sulfamoyl group; Mono- or di-C 7-16 Aralkyl-sulfamoyl group; etc. are exemplified.

[0079] The definitions of each symbol in formula (I) are described in detail below.

[0080] R1 represents R6-SO2- (where R6 represents a substituent) or an optionally substituted 1,1-dioxidotetrahydrothiopyranyl group.

[0081] Here, examples of the "substituent" represented by R6 include "optionally substituted hydrocarbon group", "optionally substituted heterocyclic group", "optionally substituted hydroxy group", "optionally substituted amino group", "optionally substituted mercapto group", "cyano group", "optionally substituted acyl group", "halogen atom", etc.

[0082] R6 is preferably an optionally substituted hydrocarbon group, more preferably a C 1-6 alkyl group (preferably methyl, ethyl).

[0083] In the "optionally substituted 1,1 - dioxidetetrahydrothiopyranyl group" represented by R1, the "1,1 - dioxidetetrahydrothiopyranyl group" may have substituents at substitutable positions, for example, 1 to 5, preferably 1 to 3 substituents. As the said "substituent", those exemplified as the substituents in the "optionally substituted C 3-8 cycloalkyl group" are used. When the "1,1 - dioxidetetrahydrothiopyranyl group" has two or more substituents, each substituent may be the same or different.

[0084] The said "substituent" is preferably a hydroxy group or the like.

[0085] R1 is preferably a C 1-6 alkylsulfonyl group (preferably methylsulfonyl, ethylsulfonyl), or a 1,1 - dioxidetetrahydrothiopyranyl group, each of which may be optionally substituted with 1 to 3 substituents selected from, for example, a hydroxy group or the like, and more preferably a C 1-6 alkylsulfonyl group (preferably methylsulfonyl, ethylsulfonyl), or a 1,1 - dioxidetetrahydrothiopyranyl group optionally substituted with a hydroxy group.

[0086] In another aspect, R1 is preferably R6 - SO2 - (where R6 represents a substituent), and more preferably a C 1-6 alkylsulfonyl group (preferably methylsulfonyl, ethylsulfonyl).

[0087] X represents a bond or a divalent hydrocarbon group.

[0088] Examples of the "divalent hydrocarbon group" represented by X include a divalent chain hydrocarbon group, a divalent cyclic hydrocarbon group, and a divalent chain - cyclic hydrocarbon group. Specifically, (1)C 1-10An alkylene group (e.g., -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -CHCH3-, -C(CH3)2-, -(CH(CH3))2-, -(CH2)2C(CH3)2-, -(CH2)3C(CH3)2-); (2)C 2-10 An alkenylene group (e.g., -CH=CH-, -CH2-CH=CH-, -CH=CH-CH2-, -CH=CH-CH2-CH2-, -C(CH3)2-CH=CH-, -CH2-CH=CH-CH2-, -CH2-CH2-CH=CH-, -CH=CH-CH=CH-, -CH=CH-CH2-CH2-CH2-); (3)C 2-10 An alkynylene group (e.g., -C≡C-, -CH2-C≡C-, -CH2-C≡C-CH2-CH2-); (4)C 3-8 A cycloalkylene group (e.g., 1,2-cyclopropylene, 1,3-cyclobutylene, 1,3-cyclopentylene, 1,3-cyclohexylene, 1,4-cyclohexylene, 1,4-cycloheptylene, 1,5-cyclooctylene); (5)C 6-14 An arylene group (e.g., phenylene (e.g., 1,2-phenylene, 1,3-phenylene, 1,4-phenylene), naphthylene (e.g., 1,2-naphthylene, 1,3-naphthylene, 1,4-naphthylene, 1,5-naphthylene, 1,6-naphthylene, 1,7-naphthylene, 1,8-naphthylene, 2,3-naphthylene, 2,6-naphthylene, 2,7-naphthylene), biphenylene (e.g., 2,2'-biphenylene, 3,3'-biphenylene, 4,4'-biphenylene), etc. The C 6-14 arylene may be partially saturated, and a partially saturated C 6-14 arylene includes, for example, tetrahydronaphthylene, etc.).; (6) Any combination of two selected from the above (1) to (5) (e.g., methylene-phenylene, phenylene-methylene, ethylene-phenylene, phenylene-ethylene, methylene-cyclohexylene, cyclohexylene-methylene, methylene-naphthylene, naphthylene-methylene); etc. may be mentioned.

[0089] X is preferably a bond or C 1-10 an alkylene group (preferably C 1-6 an alkylene group, more preferably a linear C 1-3 an alkylene group.) and more preferably C 1-6 an alkylene group (preferably a linear C 1-3 an alkylene group, more preferably -(CH2)3-).

[0090] R2 and R3 are the same or different and each represents a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group or an optionally substituted hydroxy group.

[0091] R2 and R3 are preferably the same or different and each is a hydrogen atom; a halogen atom; or C 1-6 an alkyl group (preferably methyl) and more preferably both are hydrogen atoms.

[0092] R4 and R5 are the same or different and each represents a C 1-6 alkyl group which may be substituted with a hydroxy group. R4 and R5 are preferably the same or different and each is a C 1-6 alkyl group, more preferably both are methyl.

[0093] Ring A represents a benzene ring which may further have a substituent selected from a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted hydroxy group and an optionally substituted amino group.

[0094] Ring A is preferably a halogen atom; a C 6-14 alkyl group which may be substituted with 1 to 3 C 1-6 aryloxy groups (preferably phenoxy); 1 to 3 Cs 6-14 a benzene ring which may be substituted with an aryl group (preferably phenyl) Cs 1-6 an alkoxy group; and Cs 6-14 an aryloxy group (preferably phenoxy) a benzene ring which may further have 1 to 3 substituents selected from, more preferably, a halogen atom, a C 1-6 alkyl group and a C 1-6 alkoxy group, and particularly preferably, an unsubstituted benzene ring.

[0095] Ring B represents a 5- to 7-membered ring.

[0096] Examples of the "5- to 7-membered ring" represented by Ring B include 5- to 7-membered aromatic rings such as a benzene ring and a 5- to 7-membered aromatic heterocyclic ring, and 5- to 7-membered non-aromatic rings such as a 5- to 7-membered alicyclic hydrocarbon and a 5- to 7-membered non-aromatic heterocyclic ring.

[0097] Examples of the 5- to 7-membered aromatic heterocyclic ring include 5- to 7-membered monocyclic aromatic heterocyclic rings containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom in addition to a carbon atom as ring-constituting atoms.

[0098] Preferable examples of the monocyclic aromatic heterocyclic ring include furan, thiophene, pyridine, pyrimidine, pyridazine, pyrazine, pyrrole, imidazole, pyrazole, isoxazole, isothiazole, oxazole, thiazole, oxadiazole, thiadiazole, triazole, tetrazole, triazine, and the like.

[0099] Examples of the 5- to 7-membered alicyclic hydrocarbon include saturated or unsaturated alicyclic hydrocarbons having 5 to 7 carbon atoms, such as C 5-7 cycloalkane, C 5-7 cycloalkene, and the like.

[0100] Cs 5-7Preferable examples of the cycloalkane include cyclopentane, cyclohexane, cycloheptane and the like.

[0101] C 5-7 Preferable examples of the cycloalkene include cyclopentene, cyclohexene, cycloheptene and the like.

[0102] Examples of the 5- to 7-membered non-aromatic heterocyclic ring include 5- to 7-membered monocyclic non-aromatic heterocyclic rings containing 1 to 4 heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom in addition to carbon atoms as ring-constituting atoms.

[0103] Preferable examples of the monocyclic non-aromatic heterocyclic ring include dihydrofuran, tetrahydrofuran, dihydrothiophene, tetrahydrothiophene, pyrrolidine, pyrroline, pyrazolidine, pyrazoline, piperidine, piperazine, morpholine, thiomorpholine, hexamethyleneimine, oxazolidine, oxazoline, thiazolidine, thiazoline, imidazolidine, imidazoline, azepane, oxepane, tetrahydropyridine, dihydropyridine and the like.

[0104] Ring B is preferably a 5- to 7-membered monocyclic non-aromatic heterocyclic ring, more preferably tetrahydrofuran. That is,

[0105]

Chem.

[0106] the ring represented by

[0107]

Chem.

[0108] is,

[0109]

Chem.

[0110] is.

[0111] Y represents a bond or CH2. Y is preferably CH2.

[0112] R represents an optionally substituted hydroxy group. Here, the "substituent" that the "optionally substituted hydroxy group" may have is preferably a C 1-6 alkyl group.

[0113] R is preferably a hydroxy group; or C 1-6 an alkoxy group (preferably methoxy) and more preferably a hydroxy group. In formula (I), the partial structural formula:

[0114]

Chemical formula

[0115] is preferably (2,3-dihydro-1-benzofuran-3-yl)acetic acid, that is,

[0116]

Chemical formula

[0117] is. In particular, the compound (I) having the partial structure of ((3S)-2,3-dihydro-1-benzofuran-3-yl)acetic acid is preferred because it has excellent GPR40 receptor agonist activity.

[0118] Suitable examples of compound (I) include the following compounds A to C. In particular, one of compound C, [(3S)-6-({2',6'-dimethyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid (fasiglifam), is preferred as a GPR40 agonist in the present invention.

[0119] [Compound A] R 1 but, each of which is optionally substituted by 1 to 3 substituents selected from a hydroxy group, C 1-6 an alkylsulfonyl group (preferably methylsulfonyl or ethylsulfonyl), or a 1,1-dioxidetetrahydrothiopyranyl group; [R 1 is preferably C 1-6 an alkylsulfonyl group (preferably methylsulfonyl or ethylsulfonyl), or a 1,1-dioxidetetrahydrothiopyranyl group optionally substituted with a hydroxy group; X is a bond or C 1-6 Alkylene group (preferably a straight chain C 1-3 alkylene group); R 2 and R 3 are the same or different, respectively hydrogen atoms; a halogen atom; or C 1-6 an alkyl group (preferably methyl); R 4 and R 5 are the same or different, respectively C 1-6 an alkyl group (preferably methyl); Ring A is a halogen atom, C 1-6 Alkyl groups and C 1-6 a benzene ring (preferably an unsubstituted benzene ring) which may further have 1 to 3 substituents selected from an alkoxy group; Ring B is a 5- to 7-membered monocyclic non-aromatic heterocyclic ring (preferably tetrahydrofuran); Y is CH2; and R is a hydroxy group or a C 1-6 alkoxy group [R is preferably a hydroxy group.]; Compound (I).

[0120] [Compound B] R 1 is optionally substituted with 1 to 3 substituents each selected from C 1-6 alkylsulfonyl group (preferably methylsulfonyl, ethylsulfonyl), or a 1,1-dioxidotetrahydropyranyl group [R 1 is preferably a C 1-6 alkylsulfonyl group (preferably methylsulfonyl, ethylsulfonyl), or a 1,1-dioxidotetrahydropyranyl group optionally substituted with a hydroxy group.]; X is a bond or a C 1-6 alkylene group (preferably a straight-chain C 1-3 alkylene group); R 2 and R 3 are the same or different and are each a hydrogen atom; a halogen atom; or C 1-6 alkyl group (preferably methyl); R 4 and R 5 are the same or different and are each a C 1-6 alkyl group (preferably methyl, ethyl) optionally substituted with a hydroxy group [R 4 and R 5 are preferably the same or different and are each a C 1-6 alkyl group (preferably methyl).]; Ring A is a halogen atom; 1 to 3 C 6-14 C which may be substituted with an aryloxy group (preferably phenoxy) 1-6 alkyl group; 1 to 3 C 6-14 C which may be substituted with an aryl group (preferably phenyl) 1-6 alkoxy group; and C 6-14 aryloxy group (preferably phenoxy) a benzene ring which may further have 1 to 3 substituents selected from [ring A is preferably a benzene ring which may further have 1 to 3 substituents selected from a halogen atom, C 1-6 alkyl group and C 1-6 alkoxy group, and particularly preferably an unsubstituted benzene ring.]; ring B is a 5- to 7-membered monocyclic non-aromatic heterocyclic ring (preferably tetrahydrofuran); Y is CH2; and R is a hydroxy group or C 1-6 alkoxy group [R is preferably a hydroxy group.]; Compound (I).

[0121] [Compound C] [(3S)-6-({4'-[(4-Hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy]-2',6'-dimethylbiphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid, [(3S)-6-({2',6'-Dimethyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid, [(3S)-6-({3'-Fluoro-2',6'-dimethyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid, [(3S)-6-({3'-Chloro-2',6'-dimethyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid, [(3S)-6-({3',5'-dichloro-2',6'-dimethyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid, and [(3S)-6-({2',6'-diethyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid, a compound (I) selected therefrom.

[0122] Examples of salts of the compound (I) include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids.

[0123] Preferable examples of the metal salts include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt, and barium salt; and aluminum salt.

[0124] Preferable examples of the salts with organic bases include salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, and the like.

[0125] Preferable examples of the salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.

[0126] Preferable examples of the salts with organic acids include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like.

[0127] Preferable examples of salts with basic amino acids include salts with arginine, lysine, ornithine, etc., and preferable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid, etc.

[0128] Among the above-mentioned salts, pharmaceutically acceptable salts are preferred.

[0129] The prodrug of compound (I) is a compound that is converted into compound (I) by reactions with enzymes, gastric acid, etc. under physiological conditions in vivo, that is, a compound that undergoes enzymatic oxidation, reduction, hydrolysis, etc. to change into compound (I), or a compound that undergoes hydrolysis, etc. by gastric acid, etc. to change into compound (I).

[0130] Examples of the prodrug of compound (I) include compounds in which the amino group of compound (I) is acylated, alkylated or phosphorylated (for example, compounds in which 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 in which the hydroxyl group of compound (I) is acylated, alkylated, phosphorylated or borylated (for example, compounds in which the hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated or dimethylaminomethylcarbonylated); compounds in which the carboxy group of compound (I) is esterified or amidated (for example, compounds in which the carboxy group of compound (I) is C 1-6 alkyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, phthalidyl esterified, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterified, cyclohexyloxycarbonylethyl esterified or methyl amidated); etc., and among them, compounds in which the carboxy group of compound (I) is C such as methyl, ethyl, tert-butyl, etc.1-6 Compounds esterified with an alkyl group are preferably used. These compounds can be produced from compound (I) by methods known per se.

[0131] Also, the prodrug of compound (I) may be one that changes to the compound of the present invention under physiological conditions as described on pages 163 to 198 of "Drug Development", Volume 7, Molecular Design, published by Hirokawa Shoten in 1990.

[0132] When stereoisomers exist in compound (I), these isomers are included in the present invention whether in the form of a single isomer or a mixture thereof.

[0133] Also, compound (I) may be a hydrate or an anhydrate. The hydrate of compound (I) usually has excellent storage stability.

[0134] Compound (I) may be labeled with an isotope (e.g., 3 H, 14 C, 35 S), etc.

[0135] Compound (I) or a salt thereof, or a prodrug of compound (I) has low toxicity (e.g., effects on hematological parameters such as red blood cell count, hematocrit, hemoglobin concentration, MCH, MCHC, MCV, platelet count, white blood cell count, blood reticulocyte count, white blood cell differential; blood biochemical parameters such as total protein, albumin, A / G ratio, glucose, total cholesterol, triglyceride, urea nitrogen, creatinine, total bilirubin, AST, ALT, LDH, ALP, CK, Na, K, Cl, calcium, inorganic phosphorus, retinol (vitamin A)) and few side effects (e.g., acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, drug interaction, carcinogenicity), and thus is suitable for use as an agonist of GPR40 which is the first component of the pharmaceutical composition of the present invention.

[0136] · Second component: Free fatty acid which is an endogenous ligand of GPR40 As the "free fatty acid which is an endogenous ligand of GPR40", various fatty acids are known. The "free fatty acid which is an endogenous ligand of GPR40" that can be used as the second component of the pharmaceutical composition of the present invention is not particularly limited, and can be selected from known ones while considering the effects of the present invention. Generally, medium-chain or long-chain (about 6 to 22 carbon atoms) saturated or unsaturated fatty acids, for example, saturated fatty acids having 12 to 16 carbon atoms and unsaturated fatty acids having 18 to 20 carbon atoms. In one embodiment of the present invention, the second component is preferably an unsaturated fatty acid having 18 to 20 carbon atoms such as γ-linolenic acid and docosahexaenoic acid. The position of the unsaturated bond (double bond) in the unsaturated fatty acid may be any of n-3 (ω3), n-6 (ω6), n-9 (ω9) or others, and the number of unsaturated bonds (double bonds) may be any of 1, 2, 3, 4, 5, 6. As the second component, any one of the free fatty acids which are endogenous ligands of GPR40 may be used alone, or two or more free fatty acids may be used in combination.

[0137] Specific examples of medium-chain or long-chain saturated fatty acids include caproic acid (hexanoic acid, 6:0), caprylic acid (octanoic acid, 8:0), pelargonic acid (nonanoic acid, 9:0), capric acid (decanoic acid, 10:0), lauric acid (dodecanoic acid, 12:0), myristic acid (tetradecanoic acid, 14:0), pentadecylic acid (pentadecanoic acid, 15:0), palmitic acid (hexadecanoic acid, 16:0), margaric acid (heptadecanoic acid, 17:0), stearic acid (octadecanoic acid, 18:0), arachidic acid (eicosanoic acid, 20:0), heneicosylic acid (21:0), behenic acid (docosanoic acid, 22:0).

[0138] Specific examples of medium-chain or long-chain unsaturated fatty acids include myristoleic acid (14:1, n-5), palmitoleic acid (16:1, n-7), sapienic acid (16:1, n-10), oleic acid (18:1, n-9, cis), elaidic acid (18:1, n-9, trans), vaccenic acid (18:1, n-7), gadoleic acid (20:1, n-11), eicosenoic acid (20:1, n-9), erucic acid (22:1, n-9); linoleic acid (18:2, n-6), eicosadienoic acid (20:2, n-6), docosadienoic acid (22:2, n-6); α-linolenic acid (18:3, n-3), γ-linolenic acid (18:3, n-6), pinolenic acid (18:3, n-6), α-eleostearic acid (18:3, n-5), β-eleostearic acid (18:3, n-5), mead acid (20:3, n-9), dihomo-γ-linolenic acid (20:3, n-6), eicosatrienoic acid (20:3, n-3); stearidonic acid (18:4, n-3), arachidonic acid (20:4, n-6), eicosatetraenoic acid (20:4, n-6), adrenic acid (22:4, n-6); bosseopentaenoic acid (18:5, n-4), eicosapentaenoic acid (20:5, n-3), osbond acid (22:5, n-6), sardine acid (22:5, n-3); docosahexaenoic acid (22:6, n-3).

[0139] · Use of pharmaceutical composition (pharmaceutical composition for preventing or treating bone diseases) The pharmaceutical composition of the present invention can be used for the prevention or treatment of bone diseases. "Bone diseases" are, more specifically, diseases (at least partially caused) due to bone resorption exceeding bone formation due to enhanced osteoclast activity or formation (differentiation), and can be prevented or treated by suppressing such enhancement. Such bone diseases include, for example, osteoporosis (postmenopausal osteoporosis, senile osteoporosis, secondary osteoporosis caused by the use of therapeutic agents such as steroids and hormone therapy, osteoporosis associated with rheumatoid arthritis), bone destruction associated with rheumatoid arthritis, cancerous hypercalcemia, bone destruction associated with multiple myeloma and bone metastasis of cancer, giant cell tumor, osteopenia, bone resorption around artificial joints, bone destruction in chronic osteomyelitis, Paget's disease of bone, renal osteodystrophy, osteogenesis imperfecta, psoriatic arthritis, polyarthritis secondary to various collagen diseases, alveolar bone resorption due to periodontal disease (periodontal diseases such as periapical periodontitis), alveolar bone resorption after tooth extraction, bone resorption after alveolar bone augmentation surgery, early-onset aggressive periodontitis / aggressive periodontitis / juvenile periodontitis, Marfan syndrome and related patients, Rothmund-Thomson syndrome, Beals syndrome, diseases, symptoms or conditions such as plaque-induced chronic periodontitis, bone lesions associated with traumatic osteonecrosis (such as fractures and dislocations) or non-traumatic osteonecrosis (alcohol, blood coagulation disorders, chemotherapy, corticosteroids, Cushing's syndrome, decompression sickness, Gaucher's disease, high blood lipid concentration (hyperlipidemia), liver diseases, systemic lupus erythematosus and other autoimmune connective tissue diseases, other conditions (such as chronic kidney disease and rare gene mutations), organ transplantation, pancreatitis, radiation, sickle cell disease, smoking, tumors, etc.), and other bone diseases corresponding to the following "refractory / rare diseases", etc.

[0140] In one embodiment of the present invention, the pharmaceutical composition is preferably used for the prevention or treatment of bone diseases associated with inflammation. Among the bone diseases associated with inflammation, those in the oral cavity include, for example, alveolar bone resorption due to periodontal disease (periodontal diseases such as apical periodontitis), alveolar bone resorption after tooth extraction, bone resorption after alveolar bone augmentation surgery, early-onset aggressive periodontitis / aggressive periodontitis / juvenile periodontitis, Marfan syndrome and related patients, Rothmund-Thomson syndrome, Beals syndrome, plaque-induced chronic periodontitis, and other diseases, symptoms or conditions accompanied by alveolar bone resorption (referred to as "alveolar bone resorption-related diseases, etc." in this specification). Among the bone diseases associated with inflammation, those outside the oral cavity include, for example, systemic bone diseases such as bone destruction associated with rheumatoid arthritis, bone destruction associated with multiple myeloma, psoriatic arthritis, and polyarthritis secondary to various collagen diseases.

[0141] In one embodiment of the present invention, the pharmaceutical composition is preferably used for the prevention or treatment of intractable and rare diseases having bone symptoms or pathologies of bone-related tissues (e.g., bone marrow) or blood cell pathologies in bone or bone-related tissues. Such intractable and rare diseases include, for example, the following: (a1) Diffuse idiopathic skeletal hyperostosis, (a2) Ossification of the posterior longitudinal ligament, (a3) Severe spinal stenosis, (a4) Idiopathic osteonecrosis of the femoral head, (a5) Hypophosphatasia, (a6) Vitamin D-resistant rickets / osteomalacia, (a7) Chronic recurrent multifocal osteomyelitis, (a8) Ankylosing spondylitis, (a9) Progressive fibrodysplasia ossificans, (a10) Congenital scoliosis with rib anomalies, (a11) Osteogenesis imperfecta, (a12) Thanatophoric dysplasia, (a13) Achondrogenesis; (b1) Gorham-Stout disease, (b2) Paget’s disease, (b3) Warner syndrome, (b4) Aplastic Anemia - immune aplastic anemia, etc. (or anemia accompanied by abnormal differentiation of various blood cells), (b5) Angioimmunoblastic T-Cell Lymphoma, etc. (or lymphoma accompanied by abnormal differentiation of various immune cells), (b6) adult Still's disease / AOSD / Wissler-Fanconi syndrome - systemic inflammation, joint pain, inflammation (arthritis), (b7) Aspergillosis, (b8) Autosomal Recessive Hyper IgE Syndrome, (b9) Bartonellosis / Carrion's disease / cat scratch disease / trench fever, (b10) Camurati-Engelmann Disease / diaphyseal dysplasia / Engelmann’s disease, (b11) Chordoma, (b12) Congenital Disorders of Glycosylation, (b13) Cushing Syndrome, (b14) Cystinosis, (b15) Diffuse Pulmonary Lymphangiomatosis, (b16) LAM, (b17) Graves’ Disease / Basedow disease / exophthalmic goiter / Parry disease - osteoporosis, (b18) Hepatoerythropoietic Porphyria / HEP / autosomal recessive PCT - bone loss, (b19) Hereditary Sensory and Autonomic Neuropathy Type IV / congenital insensitivity to pain with anhidrosis (CIPA) / familial dysautonomia,Type II / hereditary sensory neuropathy Type IV / HSAN IV / HSNAN4-bone loss、(b20)Hyper IgM Syndromes、(b21)Immune Thrombocytopenia-Bone marrow、(b22)Infantile Myofibromatosis / congenital generalized fibromatosis / IM / juvenile myofibromatosis、(b23)Kohler Disease / navicular osteochondrosis、(b24)Leprosy、(b25)Tuberculoid Leprosy、(b26)Leukodystrophy、(b27)Mantle Cell Lymphoma、(b28)McCune Albright Syndrome / Albright syndrome / MAS / osteitis fibrosa disseminate / PFD / POFD / polyostotic,fibrous dysplasia、(b29)Osteomyelitis-bone inflammation、(b30)Osteonecrosis / aseptic necrosis / avascular necrosis of bone / ischemic necrosis of bone、(b31)Osteoporosis / marble bone disease、(b32)Paroxysmal Nocturnal Hemoglobinuria、(b33)Progressive Multifocal Leukoencephalopathy、(b34)Pyruvate Kinase Deficiency、(b35)Rocky Mountain Spotted Fever / Sao Paulo Typhus / Tickborne Typhus Fever、(b36)Schnitzler Syndrome、(b37)Severe Chronic Neutropenia、(b38)Beta Thalassemia / Mediterranean anemia、(b39)Triosephosphate Isomerase Deficiency、(b40)Wiskott Aldrich syndrome / X-linked congenital neutropenia / X-linked thrombocytopenia / WAS Related Disorders、(b41)WHIM Syndrome / warts, hypogammaglobulinemia / infections and myelokathexis syndrome、(b42)Leishmaniasis、(b43)Autoimmune Hepatitis / lupoid hepatitis、(b44)Alpha Thalassemia、(b45)Hemophagocytic Lymphohistiocytosis、(b46)Primary Central Nervous System Lymphoma;, (c1)Acroosteolysis, (c2)Acute disease of bone, (c3)Adult osteochondrosis of spine, (c4)Adynamic bone disease, (c5)Aluminum bone disease, (c6)Apophyseal sclerosis, (c7)Astronaut-bone demineralization syndrome, (c8)Benign cortical defect of bone, (c9)Bone abscess, (c10)Bone cyst, (c11)Bone fixation device failure, (c12)Bone fixation device loosening, (c13)Bone fixation device protrusion, (c14)Bone inflammatory disease, (c15)Bone injury, (c16)Bone necrosis, (c17)Bone sequestrum, (c18)Bone turnover rate disorder, (c19)Bone widening at ends, (c20)Bony weight bearing disorder, (c21)Closed anterior dislocation of proximal end of tibia, (c22)Closed fracture dislocation of sternum, (c23)Closed lateral dislocation of proximal end of tibia, (c24)Closed medial dislocation of proximal end of tibia, (c25)Closed posterior dislocation of distal end of femur, (c26)Closed posterior dislocation of proximal end of tibia, (c27)Closed traumatic dislocation, head of fibula, (c28)Complete ankylosis of the spine, (c29)Congenital abnormalshape of arch of cervical vertebra, (c30) Congenital dysplasia of left hip, (c31) Congenital dysplasia of right hip, (c32) Congenital elevation of right scapula, (c33) Congenital glenoid dysplasia, (c34) Congenital vertical talus of left foot, (c35) Congenital vertical talus of right foot, (c36) Coracoid impingement, (c37) Craniomandibular osteopathy, (c38) Cystic dermoid choristoma of vertebra, (c39) Defect of vertebral endplate, (c40) Defect of vertebral segmentation, (c41) Deformity of bone, (c42) Degenerative disorder of bone, (c43) Dislocation of fibula, distal end, (c44) Dislocation of radius - distal, (c45) Dislocation of talus, (c46) Disorder characterized by multiple exostoses, (c47) Disorder of bone development, (c48) Disorder of bone graft, (c49) Disorder of coccyx, (c50) Disorder of continuity of bone, (c51) Disorder of epiphysis, (c52) Disorder of facial bone, (c53) Disorder of hyoid bone, (c54) Disorder of ilium, (c55) Disorder of patella, (c56) Disorder of sacrum, (c57) Disorder of sesamoid bone of foot, (c58) Disorder ofskull, (c59)Disorder of vertebra, (c60)Disproportion between fetal head and pelvis, (c61)Dysplasia with increased bone density, (c62)Enostosis of right talus, (c63)Enthesopathy of wrist and hand, (c64)Exostosis, (c65)Femoral trochlear dysplasia, (c66)Fibular ankle impingement, (c67)Foreign body in bone, (c68)Functional bone disorder, (c69)Hemangioma of bone, (c70)Hyperplasia of bone, (c71)Hypertrophic osteoarthropathy, (c72)Hypertrophy of bone, (c73)Hypoplasia of radius, (c74)Infection of bone, (c75)Intrapelvic protrusion of acetabulum, (c76)Intrapelvic protrusion of left acetabulum, (c77)Intrapelvic protrusion of right acetabulum, (c78)Kienbock's dislocation, (c79)Kissing spine, (c80)Late effect of fracture of cervical vertebra, (c81)Late effect of fracture of lumbar vertebra, (c82)Late effect of fracture of skull AND / OR face bones, (c83)Late effect of fracture of thoracic vertebra, (c84)Late effect of rickets, (c85)Lesion of bone in left ankle and / or foot, (c86)Lesion of bone of left hand, (c87)Lesion of bone ofleft radius and / or ulna、(c88)Lesion of bone of left shoulder、(c89)Lesion of bone of right hand、(c90)Lesion of bone of right radius and / or ulna、(c91)Lesion of bone of right shoulder、(c92)Lesion of left lower leg bone、(c93)Lesion of left thigh bone、(c94)Lesion of left upper arm bone、(c95)Lesion of right lower leg bone、(c96)Lesion of right thigh bone、(c97)Lesion of right upper arm bone、(c98)Lipoma co-occurrent with spina bifida、(c99)Mass of tibia、(c100)Mechanical complication of internal nail fixing device、(c101)Mechanical complication of internal plate fixing device、(c102)Mechanical complication of internal rod fixation device、(c103)Metabolic bone disease、(c104)Mis-shapen sternum、(c105)Multiple bony abnormalities、(c106)Myelocele、(c107)Navicular disease、(c108)Nelaton's dislocation、(c109)Neoplasm of bone、(c110)O / E - bone abnormal、(c111)Obstruction by bony pelvis、(c112)Open posterior dislocation of proximal end of tibia、(c113)Os acromiale、(c114)Os trigonum impingement、(c115)Osteitiscondensans, (c116) Osteitis deformans, (c117) Osteochondritis dissecans, (c118) Osteochondropathy, (c119) Osteoclasia, (c120) Osteopathy from poliomyelitis, (c121) Osteoporosis, (c122) Painful os peroneum syndrome, (c123) Partial defect of ulna, (c124) Pelvic disproportion, (c125) Pelvic obliquity, (c126) Posterior ankle impingement, (c127) Resorption of long process of incus, (c128) Retrolisthesis, (c129) Riley - Shwachman syndrome, (c130) Separation of symphysis pubis during delivery, (c131) Snapping shoulder, (c132) Spinal hydromeningocele, (c133) Spondylolisthesis, (c134) Spondylolysis, (c135) Stenosis of intervertebral foramina, (c136) Stenosis of vertebral foramen, (c137) Subacromial impingement, (c138) Subcoracoid impingement of right shoulder region, (c139) Subperiosteal hemorrhage, (c140) Tarsus enthesopathy, (c141) Total loss of ossicle, (c142) Vertebral column syndromes, (c143) Wedging of vertebra, (c144) Xiphoidalgia syndrome; (d1) Rett syndrome, (d2) Scoliosis.

[0142] Those skilled in the art can understand which diseases, etc. fall under "bone diseases", "bone diseases with inflammation in or outside the oral cavity", and "intractable / rare diseases related to bone or having bone symptoms or bone pathologies". For example, for "intractable / rare diseases", it is possible to search in databases such as the Rare Disease Center (https: / / www.nanbyou.or.jp / ), NORD (https: / / rarediseases.org / ), Orphanet (https: / / www.orpha.net / ), and SNOMED (https: / / www.findacode.com / snomed / ) using appropriate keywords (e.g., bone, bone destruction). Those skilled in the art can select diseases, etc. for which the pharmaceutical composition of the present invention is used for prevention or treatment from among diseases, etc. including not only those specifically exemplified in this specification but also those not exemplified in this specification, while considering the effects, etc. of the present invention.

[0143] In this specification, "treatment" means, in addition to completely curing the disease state, suppressing the progression and / or deterioration of symptoms even if not completely cured, halting the progression of the disease state, or improving part or all of the disease state and leading it in the direction of cure. "Prevention" means preventing, suppressing, or delaying the onset of the disease state.

[0144] The pharmaceutical composition of the present invention [a pharmaceutical composition] can be a product classified according to the legal systems of various countries, such as a product claiming the above-mentioned therapeutic or preventive effects, for example, a drug [a drug], or a quasi-drug [a quasi-drug] (medicated cosmetics) in an intermediate position between a drug and a cosmetic [a cosmetic].

[0145] The pharmaceutical composition of the present invention is formulated into an appropriate dosage form according to the bone disease to be prevented or treated, in accordance with known or well-known conventional techniques. Examples of the dosage form of the pharmaceutical composition of the present invention include oral preparations such as tablets (including sublingual tablets and orally disintegrating tablets), capsules (including soft capsules and microcapsules), granules, powders, troches, syrups, emulsions, and suspensions; and parenteral preparations such as injections (e.g., subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, drip infusions), external preparations (e.g., transdermal preparations, external solid preparations, external liquid preparations, sprays, ointments, creams, gels, patches), suppositories (e.g., rectal suppositories, vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), and eye drops. These preparations may be release-controlled preparations such as immediate-release preparations or sustained-release preparations (e.g., sustained-release microcapsules).

[0146] In a preferred embodiment of the present invention, the pharmaceutical composition of the present invention is formulated for preventing or treating alveolar bone resorption-related diseases such as periodontal disease. Such a pharmaceutical composition is preferably prepared in a dosage form suitable for local administration to a site where an alveolar bone resorption-related disease in the oral cavity has occurred or may occur, such as an external preparation (including mouthwash, dentifrice, toothpaste, etc.), tablet, troche, or injection. For example, when the pharmaceutical composition of the present invention is prepared as an external preparation, apatite or the like may be used as a base (matrix), and each active ingredient may be mixed therein to be formulated into a paste form, or a high molecular compound such as hydroxypropyl cellulose may be used as a base, and each active ingredient may be mixed therein to be formulated into a viscous external liquid preparation. The pharmaceutical composition for preventing or treating alveolar bone resorption-related diseases such as periodontal disease according to the present invention may be sold as a commercial product or may be used in medical institutions or the like in surgeries and treatments related to periodontal disease (such as periodontal tissue regeneration therapy, photodynamic therapy, maintenance, etc.).

[0147] The pharmaceutical composition of the present invention can be targeted at bone diseases in mammals. Mammals include humans and non-human mammals (non-human mammals), such as mice, rats, hamsters, guinea pigs, rabbits, dogs, cats, pigs, cows, horses, sheep, monkeys, and the like.

[0148] The pharmaceutical composition of the present invention may, if necessary, contain additional components effective for the prevention or treatment of bone diseases other than the first component and the second component. In other words, in the pharmaceutical composition of the present invention, the first component and the second component can be used in combination with known bone disease therapeutic agents (components).

[0149] Examples of known bone disease therapeutic agents include, for example, bisphosphonates (e.g., alendronate, etidronate, ibandronate, incadronate, pamidronate, risedronate, zoledronate), active vitamin D3, calcitonin and its derivatives, hormones such as estradiol, SERMs (selective estrogen receptor modulators), ipriflavone, vitamin K2 (menaquinone), calcium preparations, PTH (parathyroid hormone), non-steroidal anti-inflammatory agents (e.g., celecoxib, rofecoxib), soluble TNF receptors (etanercept, etc.), anti-TNFα antibodies or antigen-binding fragments of the antibodies (e.g., infliximab), anti-PTHrP (parathyroid hormone-related protein) antibodies or antigen-binding fragments of the antibodies, IL-1 receptor antagonists (e.g., anakinra), anti-IL-6 receptor antibodies or antigen-binding fragments of the antibodies (e.g., tocilizumab), anti-RANKL antibodies or antigen-binding fragments of the antibodies (e.g., denosumab), and OCIF (osteoclastogenesis inhibitory factor), etc.

[0150] For example, when the pharmaceutical composition of the present invention is prepared as a pharmaceutical composition for preventing or treating alveolar bone resorption-related diseases, as the additional component, a known component (periodontal disease therapeutic agent) effective for preventing or treating periodontal diseases or the like can be used in combination with the first and second components of the present invention. Examples of periodontal disease therapeutic agents include antibacterial agents (such as amoxicillin, augmentin, tetracycline, minocycline, clarithromycin, levofloxacin, clindamycin, metronidazole, etc.), anti-inflammatory agents (such as tranexamic acid, epsilon-aminocaproic acid, azulene, allantoin, allantoin chloroaluminum hydroxide, allantoin dihydroxyaluminum, glycyrrhetinic acid salts, glycyrrhetinic acids, dihydrocholesterol, cholesterol, etc.), bactericides (such as cetylpyridinium chloride, isopropylmethylphenol, sodium hypochlorite, polyethylene glycol, lauroyl sarcosine salt, hinokitiol, etc.), blood circulation promoters (such as tocopherol nicotinate, pyridoxine hydrochloride, tocopherol acetate, etc.), periodontal tissue regenerating agents (such as "Reglos" (registered trademark, Kaken Pharmaceutical Co., Ltd.) prepared from trafermin), photosensitive gels, and the like.

[0151] The pharmaceutical composition of the present invention is usually prepared as a pharmaceutical composition (formulation) containing the first and second components (and other active components as necessary) and a pharmacologically acceptable base (carrier, matrix) and other additives as necessary according to known or well-known conventional techniques. The blending amounts of various base materials and additives in the pharmaceutical composition can be appropriately adjusted in the present invention according to those in conventional known or well-known pharmaceutical compositions.

[0152] The pharmacologically provided base can be the same as those generally used in pharmaceutical compositions of various dosage forms in the present invention. For example, excipients, lubricants, binders, and disintegrants in solid preparations, solvents, solubilizing agents, suspending agents, isotonic agents, buffering agents, and soothing agents in liquid preparations, abrasives, wetting agents, binders, surfactants, etc. in paste preparations can be mentioned.

[0153] Examples of excipients include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid, and the like.

[0154] Examples of lubricants include magnesium stearate, calcium stearate, talc, colloidal silica, and the like.

[0155] Examples of binders include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose, and the like.

[0156] Examples of disintegrants include starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, L-hydroxypropyl cellulose, and the like.

[0157] Examples of solvents include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil, and the like.

[0158] Examples of solubilizers include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, and the like.

[0159] Examples of suspending agents include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropyl cellulose.

[0160] Examples of the isotonic agent include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.

[0161] Examples of the buffer include buffer solutions such as phosphates, acetates, carbonates, citrates and the like.

[0162] Examples of the soothing agent include benzyl alcohol and the like.

[0163] Examples of the abrasive include precipitated silica, silica gel, aluminosilicate, zeolite, zirconosilicate, dicalcium phosphate dihydrate and anhydride, calcium pyrophosphate, calcium carbonate, aluminum hydroxide, alumina, magnesium carbonate, magnesium phosphate tribasic, insoluble sodium metaphosphate, insoluble potassium metaphosphate, titanium oxide, hydroxyapatite, synthetic resin-based abrasives and the like.

[0164] Examples of the wetting agent include glycerin, sorbitol, propylene glycol, polyethylene glycol, 1,3-butylene glycol, xylitol, maltitol, lactitol, trehalose, torula and the like.

[0165] Examples of the binder include carrageenan, sodium carboxymethyl cellulose, sodium alginate, polyacrylic acid, sodium polyacrylate, carboxyvinyl polymer, polyvinyl alcohol, xanthan gum, tara gum, guar gum, locust bean gum, gellan gum, gelatin, curdlan, gum arabic, agar, pectin and the like.

[0166] Examples of surfactants include anionic surfactants, cationic surfactants, amphoteric surfactants, and nonionic surfactants. Examples of anionic surfactants include sodium lauryl sulfate, sodium lauroyl sarcosinate, lauroyl methyl taurine, acyl amino acid salts, sodium dodecylbenzenesulfonate, sodium α-sulfo fatty acid alkyl ester, alkyl phosphate ester salts, and the like. Examples of cationic surfactants include alkyl ammonium and alkyl benzyl ammonium salts. Examples of amphoteric surfactants include betaine-type amphoteric surfactants such as alkyl dimethylamino acetic acid betaine and fatty acid amide propyl dimethylamino acetic acid betaine, imidazoline-type amphoteric surfactants such as N-fatty acyl-N-carboxymethyl-N-hydroxyethyl ethylenediamine salts, and amino acid-type surfactants such as N-fatty acyl-L-alginate salts. Examples of nonionic surfactants include polyglycerol fatty acid esters, polyoxyethylene alkyl ethers, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid esters, sucrose fatty acid esters, sorbitan fatty acid esters, polyoxyethylene polyoxypropylene block copolymer type activators, polyoxyethylene fatty acid esters, and fatty acid monoglycerides.

[0167] Additives that are used as necessary can also be used in the present invention and are generally used in pharmaceutical compositions of various dosage forms, and examples thereof include preservatives, antioxidants, coloring agents, sweeteners, adsorbents, and wetting agents.

[0168] Examples of preservatives include para-hydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, and the like.

[0169] Examples of antioxidants include sulfites, ascorbic acid, α-tocopherol, and the like.

[0170] Examples of colorants include water-soluble edible tar dyes (e.g., edible pigments such as Edible Red No. 2 and No. 3, Edible Yellow No. 4 and No. 5, Edible Blue No. 1 and No. 2), water-insoluble lake pigments (e.g., aluminum salts of the water-soluble edible tar dyes), natural pigments (e.g., β-carotene, chlorophyll, cinnabar), and the like.

[0171] Examples of sweeteners include sodium saccharin, dipotassium glycyrrhizinate, aspartame, stevia, and the like.

[0172] The daily dosage of the pharmaceutical composition of the present invention (each of the first component, the second component, and other active ingredients used as necessary) varies depending on the type of bone disease, the degree of symptoms; the animal species, age, sex, body weight, sensitivity difference of the administration subject; the method, route, timing, interval of administration, the dosage form of the pharmaceutical composition; the type of active ingredient, etc., and is not particularly limited. For example, when preparing the pharmaceutical composition of the present invention for the prevention or treatment of bone diseases in humans, those skilled in the art can, without excessive trial and error, determine the appropriate administration method and daily dosage for human administration, or evaluate the effectiveness and safety of prevention or treatment through experiments using model animals of the bone disease and clinical trials on humans.

[0173] In one aspect of the present invention, the pharmaceutical composition of the present invention has an effect of suppressing the differentiation from hematopoietic stem cells to osteoclasts in vitro or in vivo. The suppression of the differentiation into osteoclasts can be confirmed, for example, by a decrease in the expression level of osteoclast marker genes (at least one of Ctsk, Calcr, TRAP, etc.) in the cells after culture.

[0174] In one aspect of the present invention, the pharmaceutical composition of the present invention has an effect of varying (increasing or decreasing) the expression level of a gene important for the pathological condition of a bone disease, for example, a gene related to inflammation, in vitro or in vivo. Among the "genes related to inflammation", examples of the genes whose expression levels are decreased by the pharmaceutical composition of the present invention include angiogenesis-related factors (such as Ang, Serpinb2), cytokines (such as Il-1β, Tnfsf15), and chemokines (such as Ccl7, Cxcl2). As an example, the expression level of Ang is significantly decreased by the combined use of the first component (GPR40 agonist) and the second component (free fatty acid which is an endogenous ligand of GPR40) compared to the first component alone or the second component alone.

[0175] In one aspect of the present invention, the pharmaceutical composition of the present invention has an effect of varying (increasing or decreasing) the expression level of a gene contained in a pathway related to bone metabolism and / or inflammation in vitro or in vivo. Examples of the "pathway related to bone metabolism and / or inflammation" include, for example, (A) NOD receptor signaling, (B) Toll-like receptor signaling, (C) Beta-catenin signaling, (D) MAPK signaling, (E) VEGF signaling, (F) Cytokine signaling, (G) Interferon signaling, (H) IGF-1 signaling, (I) NF-κB signaling, (J) Osteoclast signaling, (K) T-cell receptor signaling, (L) C-type lectin receptor signaling, (M) DAP-12 signaling, (N) Sphingolipid signaling, (O) Neutrophil degranulation, (P) EGFR signaling, (Q) Interleukin signaling, (R) TNF signaling.In addition, the expression levels of the genes included in these pathways, particularly the genes that do not show fluctuations in expression levels when the first component (GPR40 agonist) alone or the second component (free fatty acid, which is an endogenous ligand of GPR40) alone is used, but show fluctuations in expression levels when the first component and the second component are used in combination, include, for example, AAAS (increase), BCL2L1 (decrease), C3AR1 (decrease), CCL2 (decrease), CCL3 (decrease), CCL4 (decrease), CD36 (decrease), CSF1R (increase), CSF3 (decrease), DUSP5 (decrease), EIF4B (increase), EIF4G2 (decrease), GBP7 (decrease), GRIN1 (increase), IL7R (decrease), IP6K2 (decrease), LYN (decrease), NF1 (increase), NOS2 (decrease), PIK3CD (increase), PIM1 (decrease), PIP5K1C (increase), PLAUR (decrease), PLEKHO2 (decrease), PPP2CA (decrease), PSMA6 (decrease), PSMAY (decrease), PSMC2 (decrease), PSMD13 (decrease), PYGB (increase), RASGRP3 (increase), SDCBP (decrease), SMPD1 (decrease), SUMO1 (decrease), TNF (decrease), TNFRSF1B (decrease), TNFSF8 (decrease), TNRC6B (increase) (the content in the parentheses above indicates whether the expression level increases or decreases when the two components are used in combination compared to when no treatment is applied).

[0176] In addition, each of the various genes exemplified above can also be utilized as a biomarker (such as patient stratification, diagnostic agent, diagnostic kit, PD marker for measuring the effect in a clinical trial, etc.) regarding the use of the pharmaceutical composition of the present invention.

[0177] In each of the above aspects, the concentration of the first component (GPR40 agonist) in the medium can be, for example, in the range of 0.1 to 100 μM, and the concentration of the second component in the medium can be, for example, in the range of 0.1 to 1000 μM. When formulating the pharmaceutical composition of the present invention, in consideration of each of the above aspects, for example, taking into account the concentration in the medium, the content of the first component and the second component in the pharmaceutical composition and the daily dosage can also be adjusted.

[0178] The pharmaceutical composition of the present invention contains at least a first component and a second component, and may further contain other active ingredients as necessary. These components may be contained in a single formulation or in separate (two or more) formulations. That is, the pharmaceutical composition of the present invention may be (i) one in which each active ingredient is simultaneously administered by the same administration route with a single formulation, (ii) one in which each active ingredient is simultaneously administered by the same administration route with a plurality of formulations, (iii) one in which each active ingredient is administered with a time difference by the same administration route with a plurality of formulations, (iv) one in which each active ingredient is simultaneously administered by a plurality of administration routes with a plurality of formulations, or (v) one in which each active ingredient is administered with a time difference by a plurality of administration routes with a plurality of formulations.

[0179] -Methods and Uses- The method for preventing or treating bone diseases in mammals according to the present invention includes administering to a mammal an effective amount of a GPR40 agonist and an effective amount of a free fatty acid which is an endogenous ligand of GPR40.

[0180] The use of a GPR40 agonist and a free fatty acid which is an endogenous ligand of GPR40 according to the present invention is for manufacturing a pharmaceutical composition for preventing or treating bone diseases.

[0181] In this specification, the technical matters described in relation to the pharmaceutical composition of the present invention can be similarly applied in relation to the methods and uses according to the present invention described above.

[0182] Based on the description in this specification, the pharmaceutical composition, methods and uses of the present invention can be further converted into inventions in other aspects. For example, in one aspect, the present invention provides a method for suppressing the differentiation into osteoclasts and / or promoting the differentiation into osteoblasts, which uses a GPR40 agonist and a free fatty acid which is an endogenous ligand of GPR40 (for example, including the step of contacting with cells in vivo or in vitro).

Examples

[0183] In the following examples, Fasiglifam (TAK-875) prepared by the method described in the above-mentioned Patent Document 1 (WO2008 / 001931) was used.

[0184] [Test Example 1] Inhibitory effect on osteoclast differentiation of mouse macrophage-derived cells Osteoclasts are induced to differentiate by stimulation with RANKL (receptor activation of nuclear factor-kB ligand) produced from osteoblasts and the like by osteoclast precursor cells. In macrophage-lineage cells, which are osteoclast precursor cells, the inhibitory effect on osteoclast differentiation when a compound was treated in the presence of RANKL was examined.

[0185] For the experiment, R264.7 cells purchased from Cayman Chemical were used. The cells were suspended in DMEM containing 10% serum, seeded in a 96-well plate at a concentration of 6000 cells / well, and cultured at 37°C under 5% CO2 conditions. After overnight culture, the medium was replaced with a differentiation medium (DMEM containing 50 ng / mL RANKL and 10% serum), and simultaneously, 10 μM of free fatty acid and 10 μM of Fasiglifam were added alone or in combination. As the free fatty acid, γ-linolenic acid (SIGMA) or docosahexaenoic acid (SIGMA) was used. The medium was changed and the compounds were added every other day. On the third day of culture in the differentiation medium, the medium was removed, cell lysate (buffer RLT, RNeasy, QIAGEN) was added, and the mixture was shaken for 5 minutes to collect samples for PCR. RNA was extracted from each sample using the RNeasy 96 kit (QIAGEN), and total RNA was obtained after DNase treatment. The obtained total RNA was reverse transcribed into cDNA using SuperScript IV (Thermo Fisher), and then the expression of osteoclast marker genes (Ctsk, Calcr) was measured by quantitative PCR (ViiA7, Applied Biosystems). TaqMan Fast Advanced Master Mix (Applied Biosystems) was used as the PCR buffer, and primers and probes complementary to each gene were used from TaqMan Gene Expression Assays (Applied Biosystems). The expression level of each gene was corrected with the expression level of β-actin and shown as a relative value when the expression level of the RANKL non-added group was set to 1.0. Some cells were continuously cultured in the differentiation medium for 5 days, and on the fifth day, the cells were fixed with formalin and then stained with tartrate-resistant acid phosphatase (TRAP), an osteoclast marker, to examine the proportion of osteoclasts.

[0186] The results were as shown in Figures 1 and 2. Compared with the treatment with saturated fatty acid or Fasiglifam alone, the combined use of saturated fatty acid and Fasiglifam enhanced the inhibitory effect on osteoclast differentiation.

[0187] [Test Example 2]Combined Effect of Compounds in LPS-Stimulated Mouse Macrophage-Derived Cells The combined effect of compounds on the changes when macrophage cells were stimulated with lipopolysaccharide (LPS) derived from bacteria was examined by comprehensive gene expression analysis using RNA next-generation sequencing.

[0188] [Method] R264.7 cells purchased from KAC Co., Ltd. were used in the test. The cells were suspended in DMEM containing 10% serum, seeded in a 24-well plate at a concentration of 1.6×10 5 cells / well, and cultured under the conditions of 37°C and 5% CO2. Thirty minutes before adding LPS, 10 μM of free fatty acid and 10 μM of Fasiglifam were added alone or in combination. Stearic acid was used as the free fatty acid. After culturing for 30 minutes from the addition of the compound, LPS was added to each well at a concentration of 100 ng / mL. The same amount of PBS as LPS was added to the unstimulated control group. After culturing for 24 hours with the addition of LPS, the medium was removed, and total RNA was extracted using RNeasy (QIAGEN). mRNA was recovered from the total RNA, and library preparation was performed, followed by RNA sequencing (Illumina Hiseq). Sequencing was performed on the following 5 groups of samples, and the expression level of each gene was estimated from the obtained read count data. After determining the gene expression levels of each group, the expression levels of the target group (2) and the compound-treated groups (3, 4, 5) were compared, and genes with significantly increased or decreased expression levels (expression-variable genes) in the compound-treated groups were detected. Furthermore, pathway analysis of these expression-variable genes was performed to examine the relevance to diseases. 1) Control 2) LPS 3) LPS + free fatty acid 4) LPS + Fasiglifam 5) LPS + free fatty acid + Fasiglifam

[0189] [Results] In the comparison between the LPS group in (2) and the compound treatment groups in (3) to (5), 572 genes with expression fluctuations were detected. Among them, in genes such as angiogenesis-related factors (Ang, Serpinb2, etc.), cytokines (Il-1β, Tnfsf15, etc.), and chemokines (Ccl7, Cxcl2, etc.), a significant decrease in the expression level was observed when free fatty acid and Fasiglifam were used in combination compared to the single treatment with either free fatty acid or Fasiglifam (Figure 3). Furthermore, when pathway analysis was performed on these genes, 204 pathways were found to be related, and among them, 18 pathways (Table 1) were suggested to have a high relevance to bone metabolism and inflammation. Some of the genes with expression fluctuations included in the 18 pathways did not change with the single treatment of free fatty acid or Fasiglifam, but changes were observed only when free fatty acid and Fasiglifam were used in combination (Table 2). From these results, it was shown that when free fatty acid and Fasiglifam were used in combination, fluctuations in bone- and inflammation-related genes that were not observed with the single treatment of each compound were induced.

[0190]

Table 1

[0191]

Table 2

Claims

1. A pharmaceutical composition for preventing or treating bone diseases, comprising a GPR40 agonist and a free fatty acid which is an endogenous ligand of GPR40.

2. The pharmaceutical composition according to Claim 1, wherein the GPR40 agonist is a compound represented by the formula (I) or a salt thereof, or a prodrug of the compound represented by the formula (I). 【Chemical 1】 [In the formula (I), R １ represents R ６ -SO ２ -(R ６ represents a substituent.) or an optionally substituted 1,1-dioxidotetrahydropyranyl group; X represents a bond or a divalent hydrocarbon group; R ２ and R ３ each represents a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group or an optionally substituted hydroxy group, and may be the same or different; R ４ and R ５ each represents a C １－６ alkyl group which may be substituted with a hydroxy group, and may be the same or different; Ring A represents a benzene ring which may further have a substituent selected from the group consisting of a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted hydroxy group, and an optionally substituted amino group; Ring B represents a 5- to 7-membered ring; Y represents a linking group or CH ２ and; R represents an optionally substituted hydroxy group. ]

3. The pharmaceutical composition according to Claim 1, wherein the free fatty acid which is an endogenous ligand of GPR40 is one or more saturated or unsaturated fatty acids having 6 to 22 carbon atoms.

4. The pharmaceutical composition according to Claim 1, wherein the bone disease is a bone disease accompanied by inflammation.

5. The pharmaceutical composition according to Claim 4, wherein the bone disease accompanied by inflammation is a disease, symptom or condition accompanied by alveolar bone resorption in periodontal disease, alveolar bone resorption after tooth extraction, bone resorption after alveolar bone augmentation surgery or other alveolar bone resorption.

6. The pharmaceutical composition according to Claim 1, wherein the bone disease is a refractory / rare disease having a bone symptom or a pathological condition of a bone-related tissue or a blood cell in a bone or a tissue related to a bone.

7. A method for preventing or treating a bone disease in a mammal, comprising administering an effective amount of a GPR40 agonist and an effective amount of a free fatty acid which is an endogenous ligand of GPR40 to the mammal.

8. Use of a GPR40 agonist and a free fatty acid which is an endogenous ligand of GPR40 for producing a pharmaceutical composition for preventing or treating a bone disease.

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