Pharmaceutical composition for preventing or treating bone diseases

Abstract

The present invention provides a pharmaceutical composition that is useful for preventing or treating bone diseases relating to abnormality in the balance of osteoclasts and osteoblasts, in particular, bone diseases associated with inflammation such as periodontal disease. This pharmaceutical composition for preventing or treating bone diseases comprises a GPR40 agonist and a free fatty acid that is an endogenous ligand of GPR40.

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 technology]

[0002] GPR40 (sometimes called FFAR1 (free fatty acid receptor 1)) is a G protein-coupled receptor that is expressed in pancreatic β cells and bone-related cells (osteoclasts, osteoblasts, and their precursor cells, etc.) and uses free fatty acids as endogenous ligands. The binding of free fatty acids to GPR40 can regulate the activity of cells expressing this receptor. For example, pancreatic β cells are activated by the binding of free fatty acids to GPR40, inducing insulin secretion.

[0003] On the other hand, various GPR40 agonists (agonistic drugs) are also known, which are compounds other than free fatty acids that can bind to GPR40 and can regulate the activity of GPR40-expressing cells. For example, Patent Document 1 describes a fused ring compound represented by a specific structural formula as a GPR40 agonist, and further describes in the Examples that the compound has activity equivalent to that of free fatty acids (γ-linolenic acid) in the secretion of insulin from pancreatic β cells, and therefore may be used for the prevention or treatment of diabetes. Non-Patent Document 1 describes a list of various compounds that serve as GPR40 agonists.

[0004] One of the fused ring compounds described in Patent Document 1 is a compound known as 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 describes that the agonist Fasiglifam binds to a different site (allosteric site) of GPR40 than the endogenous ligand, free fatty acid, and that the simultaneous action of Fasiglifam and free fatty acid on GPR40 enhances insulin secretion from pancreatic β cells compared to when either acts alone.

[0005] Non-Patent Document 3 analyzes the binding modes of linolenic acid, Fasiglifam (TAK-875), and other GPR40 agonists (GW9508, TUG-770, AMG 837, AM 8182, AM 1638) to GPR40 using molecular structure models. Non-Patent Document 4 also describes in detail the binding mode of Fasiglifam (TAK-875) to GPR40 using molecular structure models. Non-Patent Documents 9 and 10 provide reviews of GPR40 agonists, and further list TUG-469, AM-5262, LY2881835, etc. as GPR40 agonists.

[0006] Furthermore, Non-Patent Document 5 studies the individual effects of various free fatty acids and a GPR40 / GPR120 agonist (GW9508) on GPR40 expressed in osteoclasts and GPR120 expressed in osteoblasts, reporting that these free fatty acids and agonists have the effect of suppressing osteoclast formation (differentiation and maturation into osteoclasts) caused by the interaction of osteoclasts (RANK) with osteoblasts (RANKL). Non-Patent Document 6 also describes, through research using a GPR40 / GPR120 agonist (GW9508), that the action of GW9508 on GPR40 suppresses differentiation into osteoclasts, thereby preventing bone loss due to ovariectomy.

[0007] Non-Patent Document 7 shows that there is a close relationship between bone metabolism due to bone resorption and bone destruction and immune responses, and describes the relationship between immune responses and bone diseases, particularly oral bone diseases that are prone to inflammation due to bacterial infection. Furthermore, Non-Patent Document 8 describes the possibility that activation of GPR40 can prevent osteoarthritis, as inflammatory mediators increase and joint destruction worsens in GPR40-deficient animals. [Prior art documents] [Patent documents]

[0008] [Non-Patent Document 1] Yonezawa et al. Free Fatty Acids-Sensing G Protein-Coupled Receptors in Drug Targeting and Therapeutics. Current Medicinal Chemistry, 2 013, Vol.20, No.31:3855-3871 [Non-patent document 2] Yabuki C, Komatsu H, Tsujihata Y, Maeda R, Ito R, et al. (20 13) A Novel Antidiabetic Drug, Fasiglifam / TAK-875, Acts as an Ago-Allosteric Modulator of FFAR1. PLoS ONE 8(10): e76280. doi:10.1371 / journal.pone.007628 0 [Non-patent document 3] Irina G. Tikhonova and Elena Poerio. Free fatty acid receptors: structural models and elucidation of ligand binding interactions. BMC St ructural Biology (2015) 15:16. DOI 10.1186 / s12900-015-0044-2 [Non-patent document 4] Srivastava et al. High-resolution structure of the human GP R40 receptor bound to allosteric agonist TAK-875. Nature VOL.513, pp. 124-12 7, September 4, 2014. doi:10.1038 / nature13494 [Non-Patent Document 5] Cornish et al. Fatty Acids Modulate Osteoclastogenesis. Endo crinology, November 2008, 149(11):5688-5695 [Non-patent document 6] Wauquier et al. The Free Fatty Acid Receptor G Protein-coupled Receptor 40 (GPR40) Protects from Bone Loss through Inhibition of Osteocl ast Differentiation. THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 288, NO. 9, pp . 6542-6551, March 1, 2013. [Non-Patent Document 7] Alvarez et al. Osteoimmunology of Oral and Maxillofacial Dis eases: Translational Applications Based on Biological Mechanisms. Frontiers Immunology 2019 Jul 18;10:1664. doi: 10.3389 / fimmu.2019.01664. [Non-patent document 8] Monfoulet et al. Deficiency of G-protein coupled receptor 40 , a lipid-activated receptor, heightens in vitro- and in vivo-induced murine osteoarthritis. Experimental Biology and Medicine 2015; 240: 854-866. doi: 10.1177 / 1535370214565078 [Non-Patent Document 9] Milligan et al. Characterizing pharmacological ligands to st udy the long-chain fatty acid receptors GPR40 / FFA1 and GPR120 / FFA4. British Journal of Pharmacology (2015) 172 3254-3265. DOI:10.1111 / bph.12879 [Non-Patent Document 10] Watterson et al. Treatment of type 2 diabetes by free fatt y acid receptor agonists. Frontiers in Endocrinology. 2014. Volume 5 | Artic le 13. doi: 10.3389 / fendo.2014.00137 [Non-patent literature]

[0009] [Non-Patent Document 1] Yonezawa et al. Free Fatty Acids-Sensing GProtein-Coupled Receptors in Drug Targeting and Therapeutics. Current MedicinalChemistry, 2013, Vol.20, No.31:3855-3871 [Non-patent document 2] Yabuki C, Komatsu H,Tsujihata Y, Maeda R, Ito R, et al. (2013) Acts of a Novel Antidiabetic Drug,Fasiglifam / TAK-875, as an Ago-Allosteric Modulator of FFAR1. PLoS ONE8(10): e76280. doi:10.1371 / journal.pone.0076280

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[0010] Osteoclasts, together with osteoblasts and osteocytes, constitute bone, and bone is remodeled (bone remodeling) through bone resorption by osteoclasts and bone formation by osteoblasts. An imbalance in the activity of osteoclasts and osteoblasts can cause various bone diseases, such as osteoporosis and rheumatoid arthritis.

[0011] Periodontal disease, caused by periodontal disease-causing bacteria, leads to increased and chronic inflammation in periodontal tissues, resulting in the destruction of bone tissue (alveolar bone), and osteoclasts are also involved in this destruction. However, bisphosphonates, which are used as osteoporosis treatments to increase bone mass by inducing apoptosis in osteoclasts and inhibiting bone resorption, have been reported to cause bisphosphonate-related osteonecrosis of the jaw (BRONJ) in periodontal disease treatments. Furthermore, even with the use of anti-RANKL antibody (denosumab), a next-generation osteoporosis treatment that inhibits the activity of RANKL, essential for osteoclast formation and differentiation, osteonecrosis of the jaw occurs in 1–2% of patients. To prevent or treat periodontal disease, it is necessary to suppress alveolar bone (jawbone) destruction in the unique environment of the oral cavity, where bacterial infection disrupts the immune balance and promotes inflammation. Therefore, new solutions are needed rather than simply relying on known osteoporosis treatments.

[0012] An objective of the present invention is to provide a pharmaceutical composition that is useful for preventing or treating bone diseases associated with an imbalance between osteoclasts and osteoblasts, particularly bone diseases accompanied by inflammation such as periodontal disease. [Means for solving the problem]

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

[0014] That is, the present invention includes the following: [Section 1] A pharmaceutical composition for preventing or treating bone diseases, comprising a GPR40 agonist and a free fatty acid that is an endogenous ligand of GPR40. [Section 2] 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). [ka] [In formula (I), R 1 is R 6 -SO2-(R 6 represents a substituent.) or an optionally substituted 1,1-dioxidetetrahydrothiopyranyl 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 5each of which is optionally substituted with a hydroxy group; 1-6 represent alkyl groups, which 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. [Section 3] Item 2. 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. [Section 4] Item 1. The pharmaceutical composition according to Item 1, wherein the bone disease is an inflammatory bone disease. [Section 5] Item 5. The pharmaceutical composition according to Item 4, wherein the bone disease accompanied by inflammation is alveolar bone resorption in periodontal disease, alveolar bone resorption after tooth extraction, bone resorption after alveolar bone augmentation, or other diseases, symptoms, or conditions accompanied by alveolar bone resorption. [Section 6] Item 1. The pharmaceutical composition according to Item 1, wherein the bone disease is an intractable or rare disease having bone symptoms in bone or bone-related tissues, pathological conditions of bone-related tissues, or pathological conditions of blood cells. [Section 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. [Section 8] Use of a GPR40 agonist and a free fatty acid that is an endogenous ligand of GPR40 for the manufacture of a pharmaceutical composition for the prevention or treatment of a bone disease. [Effects 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] FIG. 1 is a graph showing the results of the expression levels of osteoclast marker genes (Ctsk, Calcr) measured in Test Example 1. [Figure 2] FIG. 2 shows staining images of tartrate-resistant acid phosphatase (TRAP), an osteoclast marker, observed in Test Example 1. [Figure 3] FIG. 3 is a graph showing the results of the expression levels of six genes (Ang, Serpinb2, Il-1β, Tnfsf15, Ccl7, and Cxcl2) measured in Test Example 2. DETAILED DESCRIPTION OF THE INVENTION

[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] 1st ingredient: GPR40 agonist Various compounds are known as "GPR40 agonists." Examples of "GPR40 agonists" include the compounds described in Patent Document 1, as well as the compounds described in WO2004 / 041266, WO2004 / 106276, and WO2005 / 063729, which are listed in the Background Art section of Patent Document 1. Examples of "GPR40 agonists" include GW9508, TUG-770, TUG-469, AMG 837, AM 8182, AM 1638, AM-5262, and LY2881835, which are listed in Non-Patent Documents 3, 9, and 10. The list in Non-Patent Document 1 can also be referenced. The "GPR40 agonist" that can be used as the first component of the pharmaceutical composition of the present invention is not particularly limited and can be selected taking into consideration the effects of the present invention. Any one GPR40 agonist may be used alone, or two or more may be used in combination.

[0019] GPR40 agonists include those that bind to the same site on GPR40 as free fatty acids (orthosteric site), and those that bind to a site different from free fatty acids (allosteric site). The latter type of GPR40 agonist is preferred for use in the present invention.

[0020] Furthermore, medium- or long-chain free fatty acids, which are endogenous ligands of GPR40 agonists, are also endogenous ligands for GPR120 (FFAR4) in addition to GPR40. The GPR40 agonists used in the present invention may be non-selective agonists (dual agonists) that also act as agonists for GPR120 (acting as agonists for both GPR40 and GPR120), or selective agonists that do not act as agonists for GPR120 (acting only as agonists for 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 formula (I) (herein referred to as "compound (I)") or a salt thereof, or a prodrug of compound (I), which is 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] [ka]

[0023] In formula (I), R 1 is R 6 -SO2-(R 6 represents a substituent.) or an optionally substituted 1,1-dioxidetetrahydrothiopyranyl 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 of which is optionally substituted with a hydroxy group; 1-6 represent alkyl groups, which 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 term "halogen atom" used herein includes a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

[0025] Unless otherwise specified, the term "optionally substituted hydrocarbon group" used herein includes, 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 groups."

[0026] "C" in this specification 1-6 Unless otherwise specified, examples of the "alkyl group" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, and the like.

[0027] "C" in this specification 2-6 Unless otherwise specified, examples of the "alkenyl group" include vinyl, propenyl, isopropenyl, 2-buten-1-yl, 4-penten-1-yl, 5-hexen-1-yl, and the like.

[0028] "C" in this specification 2-6 Unless otherwise specified, examples of the "alkynyl group" include 2-butyn-1-yl, 4-pentyn-1-yl, 5-hexyn-1-yl, and the like.

[0029] "C" in this specification 3-8 Unless otherwise specified, examples of the "cycloalkyl group" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0030] "C" in this specification 6-14 Unless otherwise specified, examples of the "aryl group" include phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, and 2-anthryl.6-14 The aryl may be partially saturated and may be a partially saturated C 6-14 The aryl includes, for example, tetrahydronaphthyl.

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

[0032] Unless otherwise specified, the term "optionally substituted hydroxy group" used herein includes, 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."

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

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

[0035] As used herein, the "heterocyclic oxy group" includes a hydroxy group substituted by the later-described "heterocyclic group". Preferable examples of the heterocyclic oxy group include tetrahydropyranyloxy, thiazolyloxy, pyridyloxy, pyrazolyloxy, oxazolyloxy, thienyloxy, furyloxy, etc.

[0036] "C" in this specification 6-14 Unless otherwise specified, examples of the "aryloxy group" include phenoxy, 1-naphthyloxy, 2-naphthyloxy, and the like.

[0037] "C" in this specification 7-16 Unless otherwise specified, examples of the "aralkyloxy group" include benzyloxy, phenethyloxy, and the like.

[0038] Unless otherwise specified, the term "optionally substituted mercapto group" used herein includes, 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 groups, etc.

[0039] "C" in this specification 1-6 Unless otherwise specified, examples of the "alkylthio group" include 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 by the later-described "heterocyclic group". Preferable examples of the heterocyclic thio group include tetrahydropyranylthio, thiazolylthio, pyridylthio, pyrazolylthio, oxazolylthio, thienylthio, furylthio, and the like.

[0041] "C" in this specification 6-14Unless otherwise specified, examples of the "arylthio group" include phenylthio, 1-naphthylthio, 2-naphthylthio, and the like.

[0042] "C" in this specification 7-16 Unless otherwise specified, examples of the "aralkylthio group" include benzylthio and phenethylthio.

[0043] Unless otherwise specified, examples of the "heterocyclic group" used herein include 5- to 14-membered (monocyclic, bicyclic, or tricyclic) heterocyclic groups containing, as ring-constituting atoms other than carbon atoms, one or two kinds and one to four heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom, preferably (i) a 5- to 14-membered (preferably a 5- to 10-membered) aromatic heterocyclic group, and (ii) a 5- to 10-membered non-aromatic heterocyclic group. Among these, a 5- or 6-membered aromatic heterocyclic group is preferred. Specific examples include 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 Zolyl (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[ aromatic heterocyclic groups such as [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), and isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl); Examples thereof include 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), and tetrahydropyranyl.

[0044] "C" in this specification 1-6 Unless otherwise specified, examples of the "alkyl-carbonyl group" include acetyl, isobutanoyl, isopentanoyl, and the like.

[0045] "C" in this specification 1-6 Unless otherwise specified, examples of the "alkoxy-carbonyl group" include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, and the like.

[0046] "C" in this specification 3-8 Unless otherwise specified, examples of the "cycloalkyl-carbonyl group" include cyclopentylcarbonyl, cyclohexylcarbonyl, and the like.

[0047] "C" in this specification 6-14 Unless otherwise specified, examples of the "aryl-carbonyl group" include benzoyl, 1-naphthoyl, 2-naphthoyl, and the like.

[0048] "C" in this specification 7-16 Unless otherwise specified, examples of the "aralkyl-carbonyl group" include phenylacetyl, 2-phenylpropanoyl, and the like.

[0049] "C" in this specification 6-14Unless otherwise specified, examples of the "aryloxy-carbonyl group" include phenoxycarbonyl, naphthyloxycarbonyl, and the like.

[0050] "C" in this specification 7-16 Unless otherwise specified, examples of the "aralkyloxy-carbonyl group" include benzyloxycarbonyl, phenethyloxycarbonyl, and the like.

[0051] Unless otherwise specified, examples of the "nitrogen-containing heterocycle-carbonyl group" used herein include pyrrolidinylcarbonyl, piperidinocarbonyl and the like.

[0052] "C" in this specification 1-6 Unless otherwise specified, examples of the "alkylsulfonyl group" include methylsulfonyl, ethylsulfonyl, and the like.

[0053] "C" in this specification 6-14 Unless otherwise specified, examples of the "arylsulfonyl group" include phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl, and the like.

[0054] "C" in this specification 1-6 Unless otherwise specified, examples of the "alkylsulfinyl group" include methylsulfinyl, ethylsulfinyl, and the like.

[0055] "C" in this specification 6-14 Unless otherwise specified, examples of the "arylsulfinyl group" include phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl, and the like.

[0056] Unless otherwise specified, the "optionally esterified carboxyl group" in this specification includes, for example, carboxyl, C 1-6 Alkoxy-carbonyl group, C 6-14 Aryloxy-carbonyl group, C 7-16 Examples include an aralkyloxy-carbonyl group.

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

[0058] The "optionally halogenated C" in this specification 1-6 Unless otherwise specified, the "alkoxy group" includes the above "C" which may be substituted with 1 to 5 of the above "halogen atoms". 1-6 Examples of alkoxy groups include methoxy, ethoxy, isopropoxy, tert-butoxy, and trifluoromethoxy.

[0059] As used herein, "mono- or di-C 1-6 Unless otherwise specified, the "alkyl-amino group" is the same as the "C 1-6 and amino groups mono- or di-substituted with an alkyl group. Examples include methylamino, ethylamino, propylamino, dimethylamino, diethylamino, and the like.

[0060] As used herein, "mono- or di-C 6-14 Unless otherwise specified, the "aryl-amino group" is the same as the "C 6-14 and amino groups mono- or di-substituted with an "aryl group." Examples include phenylamino, diphenylamino, 1-naphthylamino, and 2-naphthylamino.

[0061] As used herein, "mono- or di-C 7-16 Unless otherwise specified, the "aralkyl-amino group" refers to the above "C 7-16 and amino groups mono- or di-substituted with an aralkyl group, such as benzylamino and phenethylamino.

[0062] "NC" in this specification 1-6 Alkyl-NC 6-14 Unless otherwise specified, the "aryl-amino group" is the same as the "C 1-6 alkyl group" and the above "C 6-14 and amino groups substituted with an "aryl group." Examples include N-methyl-N-phenylamino and N-ethyl-N-phenylamino.

[0063] "NC" in this specification 1-6 Alkyl-NC 7-16 Unless otherwise specified, the "aralkyl-amino group" refers to the above "C 1-6 alkyl group" and the above "C 7-16 and amino groups substituted with an "aralkyl group." Examples include N-methyl-N-benzylamino and N-ethyl-N-benzylamino.

[0064] As used herein, "mono- or di-C 1-6 Unless otherwise specified, the "alkyl-carbamoyl group" is the same as the "C 1-6 Examples include carbamoyl groups mono- or di-substituted with an alkyl group. Examples include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, and ethylmethylcarbamoyl.

[0065] As used herein, "mono- or di-C 6-14 Unless otherwise specified, the "aryl-carbamoyl group" is the same as the "C 6-14 and carbamoyl groups mono- or di-substituted with an aryl group. Examples include phenylcarbamoyl, 1-naphthylcarbamoyl, and 2-naphthylcarbamoyl.

[0066] As used herein, "mono- or di-C 3-8 Unless otherwise specified, the "cycloalkyl-carbamoyl group" includes the above-mentioned "C 3-8 and carbamoyl groups mono- or di-substituted with "cycloalkyl groups." Examples include cyclopropylcarbamoyl.

[0067] As used herein, "mono- or di-C 7-16 Unless otherwise specified, the "aralkyl-carbamoyl group" refers to the above "C 7-16 and carbamoyl groups mono- or di-substituted with an aralkyl group. For example, benzylcarbamoyl is mentioned.

[0068] Unless otherwise specified, the "mono- or di-5- to 7-membered heterocyclyl-carbamoyl group" used herein includes carbamoyl groups mono- or di-substituted with 5- to 7-membered heterocyclic groups. Here, the 5- to 7-membered heterocyclic group includes a heterocyclic group containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms of 1 or 2 kinds selected from nitrogen atom, sulfur atom, and oxygen atom. Preferred examples of the "mono- or di-5- to 7-membered heterocyclyl-carbamoyl group" include 2-pyridylcarbamoyl, 3-pyridylcarbamoyl, 4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl, etc.

[0069] As used herein, "mono- or di-C 1-6 Unless otherwise specified, the "alkyl-sulfamoyl group" is the same as the above "C 1-6 Sulfamoyl groups mono- or di-substituted with an alkyl group are used, and examples thereof include methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, and diethylsulfamoyl.

[0070] As used herein, "mono- or di-C 6-14 Unless otherwise specified, the "aryl-sulfamoyl group" is the same as the above "C 6-14 Sulfamoyl groups mono- or di-substituted with an "aryl group" are used, and examples thereof include phenylsulfamoyl, diphenylsulfamoyl, 1-naphthylsulfamoyl, and 2-naphthylsulfamoyl.

[0071] As used herein, "mono- or di-C 7-16 Unless otherwise specified, the "aralkyl-sulfamoyl group" refers to the above "C7-16 and sulfamoyl groups mono- or di-substituted with an aralkyl group. For example, benzylsulfamoyl is mentioned.

[0072] As used herein, the term "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 Examples of the "alkylthio group" include: (1) halogen atoms; (2) hydroxy group; (3) amino group; (4) nitro group; (5) cyano group; (6) Halogen atoms, hydroxy groups, amino groups, nitro groups, cyano groups, 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 groups, 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 Alkyl sulfonyl 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 a heterocyclic group optionally substituted by 1 to 3 substituents selected from an aryl-sulfamoyl group (preferably furyl, pyridyl, thienyl, pyrazolyl, thiazolyl, or oxazolyl); (7) Mono- or di-C1-6 Alkyl-amino groups; (8) Mono- or di-C 6-14 aryl-amino groups; (9) Mono- or di-C 7-16 Aralkyl-amino group; (10)NC 1-6 Alkyl-NC 6-14 aryl-amino groups; (11)NC 1-6 Alkyl-NC 7-16 Aralkyl-amino group; (12)C 3-8 cycloalkyl groups; (13) Optionally halogenated C 1-6 alkoxy groups; (14)C 1-6 Alkylthio groups; (15)C 1-6 alkylsulfinyl group; (16)C 1-6 Alkylsulfonyl groups; (17) a carboxyl group which may be esterified; (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 heterocyclyl-carbamoyl group; (26) C optionally substituted with a carboxyl group 1-6 Alkyl-carbonylamino groups (e.g., acetylamino, propionylamino); (27) Halogen atoms, hydroxy groups, amino groups, nitro groups, cyano groups, optionally halogenated C 1-6 Alkyl group, mono- or di-C1-6 Alkyl-amino group, C 6-14 Aryl group, mono- or di-C 6-14 Aryl-amino group, C 3-8 Cycloalkyl groups, 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 Alkyl sulfonyl 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 C optionally substituted by 1 to 3 substituents selected from aryl-sulfamoyl groups 6-14 aryloxy groups; (28) Halogen atoms, hydroxy groups, amino groups, nitro groups, cyano groups, 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 groups, 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 Alkyl sulfonyl 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 C optionally substituted by 1 to 3 substituents selected from aryl-sulfamoyl groups6-14 aryl groups; (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 atoms, hydroxy groups, amino groups, nitro groups, cyano groups, 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 groups, 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 Alkyl sulfonyl 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 C optionally substituted by 1 to 3 substituents selected from aryl-sulfamoyl groups 7-16 aralkyloxy groups; and the like, each of which may have 1 to 5 substituents selected from the following at substitutable positions: 1-6 alkyl group," "C 2-6 alkenyl group," "C 2-6 alkynyl group," "C 1-6 Alkoxy group" and "C 1-6 alkylthio groups.

[0073] As used herein, the term "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 Examples of the "aralkylthio group" include: (1) halogen atoms; (2) hydroxy group; (3) amino group; (4) nitro group; (5) cyano group; (6) optionally substituted C 1-6 alkyl groups; (7) optionally substituted C 2-6 alkenyl groups; (8) optionally substituted C 2-6 Alkynyl groups; (9) Halogen atoms, hydroxy groups, amino groups, nitro groups, cyano groups, 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 groups, 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 Alkyl sulfonyl 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 6-14C optionally substituted by 1 to 3 substituents selected from aryl-sulfamoyl groups 6-14 aryl groups; (10) Halogen atoms, hydroxy groups, amino groups, nitro groups, cyano groups, 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 groups, 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 Alkyl sulfonyl 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 C optionally substituted by 1 to 3 substituents selected from aryl-sulfamoyl groups 6-14 aryloxy groups; (11) Halogen atoms, hydroxy groups, amino groups, nitro groups, cyano groups, 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 groups, 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 Alkyl sulfonyl group, optionally esterified carboxyl group, carbamoyl group, thiocarbamoyl group, mono- or di-C 1-6Alkyl-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 C optionally substituted by 1 to 3 substituents selected from aryl-sulfamoyl groups 7-16 aralkyloxy groups; (12) Halogen atoms, hydroxy groups, amino groups, nitro groups, cyano groups, 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 groups, 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 Alkyl sulfonyl 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 a heterocyclic group optionally substituted by 1 to 3 substituents selected from an aryl-sulfamoyl group (preferably furyl, pyridyl, thienyl, pyrazolyl, thiazolyl, or oxazolyl); (13) Mono- or di-C 1-6 Alkyl-amino groups; (14) Mono- or di-C 6-14 aryl-amino groups; (15) Mono- or di-C 7-16 Aralkyl-amino group; (16)NC 1-6 Alkyl-NC 6-14 aryl-amino groups; (17)NC 1-6Alkyl-NC 7-16 Aralkyl-amino group; (18)C 3-8 cycloalkyl groups; (19) optionally substituted C 1-6 alkoxy groups; (20) optionally substituted C 1-6 Alkylthio groups; (21)C 1-6 alkylsulfinyl group; (22)C 1-6 Alkylsulfonyl groups; (23) an 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 heterocyclyl-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) C optionally substituted with a carboxyl group 1-6 Alkyl-carbonylamino groups (e.g., acetylamino, propionylamino); (36) Heterocyclic oxy group; and the like, each of which may have 1 to 5 substituents selected from the following at substitutable positions: 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 groups."

[0074] Unless otherwise specified, the "optionally substituted amino group" used herein includes (1) optionally substituted C 1-6 alkyl groups; (2) optionally substituted C 2-6 alkenyl groups; (3) optionally substituted C 2-6 Alkynyl groups; (4) optionally substituted C 3-8 cycloalkyl groups; (5) optionally substituted C 6-14 aryl groups; (6) optionally substituted C 1-6 alkoxy groups; (7) an optionally substituted acyl group; (8) an optionally substituted heterocyclic group (preferably furyl, pyridyl, thienyl, pyrazolyl, thiazolyl, or oxazolyl); (9) sulfamoyl group; (10) Mono- or di-C 1-6 Alkyl-sulfamoyl group; (11) Mono- or di-C 6-14 Aryl-sulfamoyl group; and the like. When the "optionally substituted amino group" is an amino group substituted with two substituents, these substituents may, together with the adjacent nitrogen atom, form a nitrogen-containing heterocycle. Examples of the "nitrogen-containing heterocycle" include 5- to 7-membered nitrogen-containing heterocycles containing at least one nitrogen atom as a ring-constituting atom other than carbon atoms and optionally containing 1 to 2 heteroatoms selected from oxygen atoms, sulfur atoms, and nitrogen atoms. Suitable examples of the nitrogen-containing heterocycle include pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine, thiazolidine, oxazolidine, etc.

[0075] Unless otherwise specified, the "optionally substituted acyl group" used herein includes a group represented by the formula: -COR 7 , -CO-OR 7 , -SO2R 7 , -SOR 7 , -PO(OR 7 )(OR 8 ), -CO-NR 7a R 8a and -CS-NR 7a R 8a [In the formula, R 7 and R 8 are the same or different and represent a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group; R 7a and R 8a are the same or different and represent 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 heterocycle together with the adjacent nitrogen atom.

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

[0077] The nitrogen-containing heterocycle may have one or two substituents at substitutable positions. Examples of such substituents include a hydroxy group, an optionally halogenated C 1-6 Alkyl group, C 6-14 Aryl group, C 7-16 Examples include aralkyl groups.

[0078] Suitable examples of the "optionally substituted acyl group" include: Formyl group; carboxyl group; Carbamoyl group; C 1-6 Alkyl-carbonyl group; C 1-6 Alkoxy-carbonyl groups; C 3-8 cycloalkyl-carbonyl group; C 6-14 aryl-carbonyl group; C 7-16 aralkyl-carbonyl group; C 6-14 Aryloxy-carbonyl group; C 7-16 aralkyloxy-carbonyl group; Mono- or di-C 1-6 Alkyl-carbamoyl group; Mono- or di-C 6-14 Aryl-carbamoyl group; Mono- or di-C 3-8 cycloalkyl-carbamoyl group; Mono- or di-C 7-16 Aralkyl-carbamoyl group; C 1-6 Alkylsulfonyl groups; C optionally substituted with a nitro group 6-14 arylsulfonyl groups; Nitrogen-containing heterocycles - carbonyl groups; 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; Examples include:

[0079] The definition of each symbol in formula (I) is explained in detail below.

[0080] R 1 is R 6 -SO2-(R 6 indicates a substituent) or an optionally substituted 1,1-dioxidetetrahydrothiopyranyl group.

[0081] where R 6 Examples of the "substituent" represented by the formula (I) include an "optionally substituted hydrocarbon group", an "optionally substituted heterocyclic group", an "optionally substituted hydroxy group", an "optionally substituted amino group", an "optionally substituted mercapto group", a "cyano group", an "optionally substituted acyl group", a "halogen atom", and the like.

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

[0083] R 1 The "1,1-dioxidetetrahydrothiopyranyl group" in the "optionally substituted 1,1-dioxidetetrahydrothiopyranyl group" represented by the following formula (I) may have, for example, 1 to 5, preferably 1 to 3, substituents at substitutable positions. Examples of the "substituents" include those mentioned above in the "optionally substituted C 3-8 The same substituents as those exemplified as the substituents in the "cycloalkyl group" are used. When the "1,1-dioxidetetrahydrothiopyranyl group" has two or more substituents, the respective substituents may be the same or different.

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

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

[0086] In another embodiment, R 1 is preferably R 6 -SO2-(R 6 represents a substituent), and more preferably, C 1-6 An alkylsulfonyl group (preferably, methylsulfonyl or 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, and specific examples thereof include: (1)C 1-10 Alkylene groups (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 Alkenylene groups (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 Alkynylene groups (e.g., -C≡C-, -CH2-C≡C-, -CH2-C≡C-CH2-CH2-); (4) C 3-8 cycloalkylene groups (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 Arylene groups (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. 6-14 The arylene may be partially saturated, and may be a partially saturated C 6-14 Examples of arylene include tetrahydronaphthylene; (6) A combination of any 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); Examples include:

[0089] X is preferably a bond or C 1-10 Alkylene groups (preferably C 1-6 alkylene groups, more preferably linear C 1-3 is an alkylene group.) and more preferably, C 1-6 Alkylene group (preferably a straight chain C 1-3 An alkylene group, more preferably —(CH 2 ) 3 —.

[0090] R 2 and R 3 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] R 2 and R 3 are preferably the same or different, hydrogen atoms; a halogen atom; or C 1-6 an alkyl group (preferably methyl) and more preferably, both are hydrogen atoms.

[0092] R 4 and R 5 are the same or different and each may be substituted with a hydroxy group. 1-6 Indicates an alkyl group. R 4 and R 5 are preferably the same or different, and each C 1-6 They are alkyl groups, and more preferably both are methyl.

[0093] Ring A is 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 halogen atoms; 1 to 3 Cs 6-14 C optionally substituted with an aryloxy group (preferably phenoxy) 1-6 alkyl groups; 1 to 3 Cs 6-14 C optionally substituted with an aryl group (preferably phenyl) 1-6 alkoxy groups; and C 6-14 an aryloxy group (preferably phenoxy); is a benzene ring which may further have 1 to 3 substituents selected from, more preferably a halogen atom, C 1-6 Alkyl groups and C 1-6 It is a benzene ring which may further have 1 to 3 substituents selected from alkoxy groups, and particularly preferred is an unsubstituted benzene ring.

[0095] Ring B is 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 heterocycle, 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 heterocycle.

[0097] Examples of the 5- to 7-membered aromatic heterocycle include 5- to 7-membered monocyclic aromatic heterocycles containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from oxygen atoms, sulfur atoms, and nitrogen atoms.

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

[0099] The 5- to 7-membered alicyclic hydrocarbon includes saturated or unsaturated alicyclic hydrocarbons having 5 to 7 carbon atoms, for example, C 5-7 Cycloalkane, C 5-7 Cycloalkenes and the like.

[0100] C 5-7 Suitable examples of the cycloalkane include cyclopentane, cyclohexane, and cycloheptane.

[0101] C 5-7 Suitable examples of cycloalkenes include cyclopentene, cyclohexene, and cycloheptene.

[0102] Examples of the 5- to 7-membered non-aromatic heterocycle include 5- to 7-membered monocyclic non-aromatic heterocycles containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from oxygen atoms, sulfur atoms, and nitrogen atoms.

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

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

[0105] [ka]

[0106] The ring shown by

[0107] [ka]

[0108] and particularly preferably

[0109] [ka]

[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 C 1-6 It is an alkyl group.

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

[0114] [ka]

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

[0116] [ka]

[0117] In particular, compound (I) having a 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 4and 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 heterocycle (preferably tetrahydrofuran); Y is CH; and R is a hydroxy group or C 1-6 is an alkoxy group [R is preferably a hydroxy group.]; Compound (I).

[0120] [Compound B] 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 5are the same or different and each may be substituted with a hydroxy group; 1-6 an alkyl group (preferably methyl or ethyl); [R 4 and R 5 are preferably the same or different, and each C 1-6 an alkyl group (preferably methyl)]; Ring A is halogen atoms; 1 to 3 Cs 6-14 C optionally substituted with an aryloxy group (preferably phenoxy) 1-6 alkyl groups; 1 to 3 Cs 6-14 C optionally substituted with an aryl group (preferably phenyl) 1-6 alkoxy groups; and C 6-14 an aryloxy group (preferably phenoxy); [Ring A is preferably a halogen atom, C 1-6 Alkyl groups and C 1-6 a benzene ring which may further have 1 to 3 substituents selected from an alkoxy group, and particularly preferably an unsubstituted benzene ring; Ring B is a 5- to 7-membered monocyclic non-aromatic heterocycle (preferably tetrahydrofuran); Y is CH; and R is a hydroxy group or C 1-6 is an alkoxy group [R is preferably a hydroxy group.]; Compound (I).

[0121] [Compound C] [(3S)-6-({4'-[(4-hydroxy-1,1-dioxidetetrahydro-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 Compound (I) selected from [(3S)-6-({2',6'-diethyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid.

[0122] Examples of salts of 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] Suitable examples of metal salts include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts, magnesium salts and barium salts; and aluminum salts.

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

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

[0126] Suitable examples of 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] Suitable examples of salts with basic amino acids include salts with arginine, lysine, ornithine, and suitable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid, and the like.

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

[0129] A prodrug of compound (I) refers to a compound that is converted to compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in a living body, i.e., a compound that is converted to compound (I) by enzymatic oxidation, reduction, hydrolysis, or the like, or a compound that is converted to compound (I) by hydrolysis, etc., caused by gastric acid, or the like.

[0130] Prodrugs 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 borated (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 carboxyl group of compound (I) is esterified or amidated (for example, compounds in which the carboxyl group of compound (I) is C 1-6alkyl 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 methylamidized compounds; among these, compounds in which the carboxy group of compound (I) is methyl, ethyl, tert-butyl or the like C 1-6 Compounds esterified with alkyl groups are preferably used. These compounds can be produced from compound (I) by known methods.

[0131] Furthermore, the prodrug of compound (I) may be one that is converted into the compound of the present invention under physiological conditions as described in "Drug Development," Vol. 7, Molecular Design, pp. 163 to 198, Hirokawa Publishing, 1990.

[0132] When compound (I) has stereoisomers, the present invention includes both the isomers alone and mixtures thereof.

[0133] Compound (I) may be a hydrate or a non-hydrate. Hydrates of compound (I) usually have excellent storage stability.

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

[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 value, hemoglobin concentration, MCH, MCHC, MCV, platelet count, white blood cell count, blood reticulocyte count, and differential white blood cell count; and blood biochemical parameters such as total protein, albumin, A / G ratio, glucose, total cholesterol, triglycerides, urea nitrogen, creatinine, total bilirubin, AST, ALT, LDH, ALP, CK, Na, K, Cl, calcium, inorganic phosphorus, and retinol (vitamin A)) and few side effects (e.g., acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, drug interactions, and carcinogenicity), and is therefore suitable for use as a GPR40 agonist, which is the first ingredient of the pharmaceutical composition of the present invention.

[0136] Second component: Free fatty acids, which are endogenous ligands of GPR40 Various fatty acids are known as "free fatty acids that are endogenous ligands of GPR40." The "free fatty acids that are endogenous ligands of GPR40" that can be used as the second component of the pharmaceutical composition of the present invention are not particularly limited and can be selected from known free fatty acids while taking into consideration the effects of the present invention. Generally, however, they are medium- or long-chain (approximately 6 to 22 carbon atoms) saturated or unsaturated fatty acids, such as saturated fatty acids with 12 to 16 carbon atoms and unsaturated fatty acids with 18 to 20 carbon atoms. In one embodiment of the present invention, the second component is preferably an unsaturated fatty acid with 18 to 20 carbon atoms, such as γ-linolenic acid or docosahexaenoic acid. The position of the unsaturated bond (double bond) in the unsaturated fatty acid may be n-3 (ω3), n-6 (ω6), n-9 (ω9), or any other position, and the number of unsaturated bonds (double bonds) may be one, two, three, four, five, or six. As the second component, any one of the free fatty acids that 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- 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 (icosanoic acid, 20:0), heneicosanoic acid (21:0), and behenic acid (docosanoic acid, 22:0).

[0138] Specific examples of medium- or long-chain unsaturated fatty acids include myristoleic acid (14:1, n-5), palmitoleic acid (16:1, n-7), sabienoic 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), and pinolenic acid (18:3, n-6). These include: 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), osbondoic acid (22:5, n-6), sardonic acid (22:5, n-3); and 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. More specifically, "bone diseases" are diseases caused by (or at least contributed to by) bone resorption exceeding bone formation due to increased osteoclast activity or formation (differentiation), and can be prevented or treated by inhibiting this increase. Such bone diseases include, for example, osteoporosis (postmenopausal osteoporosis, senile osteoporosis, secondary osteoporosis due to the use of therapeutic drugs such as steroids or hormone therapy, and osteoporosis associated with rheumatoid arthritis), bone destruction associated with rheumatoid arthritis, cancer-related hypercalcemia, bone destruction associated with multiple myeloma or bone metastasis of cancer, giant cell tumor, osteopenia, osteolysis 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 periodontitis), alveolar bone resorption after tooth extraction, bone resorption after alveolar bone augmentation, early-onset aggressive periodontitis / aggressive periodontitis / juvenile periodontitis, and These include diseases, symptoms, or conditions such as periodontitis, Marfan syndrome and related patients, Loeys-Dietz syndrome, Beals syndrome, and plaque-induced chronic periodontitis; bone lesions associated with traumatic osteonecrosis (such as fractures and dislocations) or non-traumatic osteonecrosis (such as those associated with alcohol, blood clotting disorders, chemotherapy, corticosteroids, Cushing's syndrome, decompression sickness, Gaucher disease, high blood lipid levels (hyperlipidemia), liver disease, systemic lupus erythematosus and other autoimmune connective tissue diseases, other conditions (such as chronic kidney disease and rare gene mutations), organ transplants, pancreatitis, radiation, sickle cell disease, smoking, and tumors); and other bone diseases that fall under the category of "intractable or rare diseases" listed below.

[0140] In one embodiment of the present invention, the pharmaceutical composition is preferably used for the prevention or treatment of inflammatory bone diseases. Among inflammatory bone diseases occurring within the oral cavity, examples include alveolar bone resorption due to periodontal disease (periodontal diseases such as periodontitis), alveolar bone resorption after tooth extraction, bone resorption after alveolar bone augmentation, early-onset aggressive periodontitis / aggressive periodontitis / juvenile periodontitis, Marfan syndrome and related patients, Loeys-Dietz syndrome, Beales syndrome, plaque-induced chronic periodontitis, and other diseases, symptoms, or conditions associated with alveolar bone resorption (referred to herein as "alveolar bone resorption-related diseases, etc."). Among inflammatory bone diseases occurring outside the oral cavity, examples include 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 or rare diseases having bone symptoms, bone-related tissue pathologies, or blood cell pathologies in bone or bone-related tissues (e.g., bone marrow). Examples of such intractable or rare diseases include: (a1) Ossification of the ligamentum flavum, (a2) Ossification of the posterior longitudinal ligament, (a3) ​​Massive spinal stenosis, (a4) Idiopathic necrosis of the femoral head, (a5) Hypophosphatasia, (a6) Vitamin D-resistant rickets / osteomalacia, (a7) Chronic relapsing multifocal osteomyelitis, (a8) Ankylosing spondylitis, (a9) Fibrodysplasia ossificans progressiva, (a10) Congenital scoliosis with rib abnormalities, (a11) Osteogenesis imperfecta, (a12) Thanatophoric dysplasia, (a13) Achondroplasia; (b1) Gorham-Stout disease, (b2) Paget's disease, (b3) Warner syndrome, (b4) Aplastic anemia - immune aplastic anemia, etc. (or anemia with various abnormalities in the differentiation of blood cells), (b5) Angioimmunoblastic T-cell lymphoma, etc. (or lymphoma with various abnormalities in the differentiation of immune cells), (b6) adult Still's disease / AOSD / Wissler-Fanconi syndrome - systemic inflammatory, 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 will understand what diseases fall under the category of "bone diseases," "bone diseases associated with inflammation" in the oral cavity or outside the oral cavity, and "intractable or rare diseases related to bone, or with bone symptoms or pathological conditions." For example, "intractable or rare diseases" can be searched for using appropriate keywords (e.g., bone, bone destruction) in databases such as the Japan Intractable Disease Center (https: / / www.nanbyou.or.jp / ), NORD (https: / / rarediseases.org / ), Orphanet (https: / / www.orpha.net / ), and SNOMED (https: / / www.findacode.com / snomed / ). Those skilled in the art will be able to select diseases for which the pharmaceutical composition of the present invention can be used for prevention or treatment from among not only those specifically exemplified herein but also those not exemplified herein, taking into account the effects and other factors of the present invention.

[0143] As used herein, "treatment" means not only completely curing a pathological condition, but also suppressing the progression and / or worsening of symptoms, even if not completely curing, stopping the progression of the pathological condition, or improving part or all of the pathological condition and leading to a cure, and "prevention" means preventing, suppressing, or delaying the onset of the pathological condition.

[0144] In accordance with the legal systems of each country, the pharmaceutical composition of the present invention may be classified as a product that claims to have the above-mentioned therapeutic or preventive effects, such as a drug, or a quasi-drug (cosmeceutical product) that is positioned somewhere between a drug and 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, using known or commonly used techniques. Examples of dosage forms 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, lozenges, syrups, emulsions, and suspensions; and parenteral preparations such as injections (e.g., subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, and infusions), topical preparations (e.g., transdermal preparations, topical solid preparations, topical liquid preparations, sprays, ointments, creams, gels, and patches), suppositories (e.g., rectal suppositories and vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), and eye drops. These preparations may be immediate-release preparations or controlled-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 pharmaceutical compositions are preferably prepared in dosage forms suitable for local administration to sites in the oral cavity where alveolar bone resorption-related diseases have or may occur, such as topical preparations (including mouthwash, toothpaste, tooth powder, etc.), tablets, lozenges, or injections. For example, when preparing the pharmaceutical composition of the present invention as a topical preparation, apatite or other base (matrix) can be used to formulate a paste by mixing the active ingredients therein, or a polymeric compound such as hydroxypropyl cellulose can be used as a base to formulate a viscous topical liquid by mixing the active ingredients therein. The pharmaceutical composition of the present invention for preventing or treating alveolar bone resorption-related diseases such as periodontal disease may be commercially available or may be used in medical institutions for surgery or treatment related to periodontal disease (e.g., periodontal tissue regeneration therapy, photodisinfection therapy, maintenance, etc.).

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

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

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

[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, a known component (periodontal disease therapeutic agent) effective for preventing or treating periodontal disease or the like can be used as the additional component in combination with the first and second components of the present invention. Examples of periodontal disease therapeutic agents include antibacterial agents (amoxicillin, augmentin, tetracycline, minocycline, clarithromycin, levofloxacin, cyclospor ... Kisa anti-inflammatory drugs (tranexamic acid, epsilon-aminocaproic acid, azulene, arabinose, etc.), hmm Examples of anti-inflammatory agents include benzoyl perfume, ...

[0151] The pharmaceutical composition of the present invention is usually prepared as a pharmaceutical composition (preparation) containing the first and second ingredients (and optionally other active ingredients), a pharmacologically acceptable base (carrier, matrix), and optionally other additives, according to known or commonly used techniques. The amounts of various base materials and additives in the pharmaceutical composition can be appropriately adjusted in the present invention in accordance with conventional known or commonly used pharmaceutical compositions.

[0152] As pharmacological bases, those generally used in pharmaceutical compositions of various dosage forms can also be used in the present invention, and examples thereof include excipients, lubricants, binders and disintegrants in solid preparations; solvents, solubilizers, suspending agents, isotonicity agents, buffers and soothing agents in liquid preparations; and abrasives, wetting agents, binders and surfactants in paste preparations.

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

[0154] Lubricants include, for example, magnesium stearate, calcium stearate, talc, colloidal silica, and the like.

[0155] Examples of binders include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methyl cellulose, and sodium carboxymethyl cellulose.

[0156] Examples of disintegrants include starch, carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylstarch sodium, and L-hydroxypropylcellulose.

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

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

[0159] Examples of suspending agents include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate; and hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose.

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

[0161] Examples of the buffering agent include buffer solutions such as phosphate, acetate, carbonate, and citrate.

[0162] An example of the soothing agent is benzyl alcohol.

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

[0164] Examples of humectants include glycerin, sorbitol, propylene glycol, polyethylene glycol, 1,3-butylene glycol, xylitol, maltitol, lactite, trehalose, and tornare.

[0165] Examples of binders include carrageenan, sodium carboxymethylcellulose, 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, and pectin.

[0166] 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, acylamino acid salts, sodium dodecylbenzenesulfonate, sodium α-sulfofatty acid alkyl esters, and alkyl phosphate ester salts. Examples of cationic surfactants include alkylammonium salts and alkylbenzylammonium salts. Examples of amphoteric surfactants include acetate betaine-type amphoteric surfactants such as alkyldimethylaminoacetic acid betaine and fatty acid amidopropyldimethylaminoacetic acid betaine, imidazoline-type amphoteric surfactants such as N-fatty acid acyl-N-carboxymethyl-N-hydroxyethylethylenediamine salts, and amino acid-type surfactants such as N-fatty acid acyl-L-alginate salts. Examples of nonionic surfactants include polyglycerin 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 surfactants, polyoxyethylene fatty acid esters, and fatty acid monoglycerides.

[0167] As additives to be used as needed, those generally used in pharmaceutical compositions of various dosage forms can also be used in the present invention, such as preservatives, antioxidants, coloring agents, sweetening agents, adsorbents, and humectants.

[0168] Examples of preservatives include parahydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid.

[0169] Antioxidants include, for example, sulfites, ascorbic acid, α-tocopherol, and the like.

[0170] Examples of coloring agents include water-soluble food tar dyes (e.g., food dyes such as Food Red No. 2 and No. 3, Food Yellow No. 4 and No. 5, and Food Blue No. 1 and No. 2), water-insoluble lake dyes (e.g., aluminum salts of the above-mentioned water-soluble food tar dyes), and natural dyes (e.g., β-carotene, chlorophyll, and red iron oxide).

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

[0172] The daily dose of the pharmaceutical composition of the present invention (each of the first ingredient, second ingredient, and other active ingredients used as needed) is not particularly limited and varies depending on the type of bone disease, the severity of symptoms, the species, age, sex, weight, and sensitivity of the animal to be administered, the method, route, timing, and interval of administration, the dosage form of the pharmaceutical composition, the type of active ingredient, etc. For example, when the pharmaceutical composition of the present invention is prepared for the prevention or treatment of bone disease in humans, a person skilled in the art can determine the appropriate administration method and daily dose when administered to humans and evaluate the efficacy and safety of the prevention or treatment through experiments using model animals of the bone disease or clinical trials on humans, without undue trial and error.

[0173] In one aspect of the present invention, the pharmaceutical composition of the present invention has the effect of inhibiting the differentiation of hematopoietic stem cells into osteoclasts in vitro or in vivo. The inhibition of osteoclast differentiation 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 cultured cells.

[0174] In one aspect of the present invention, the pharmaceutical composition of the present invention exerts an effect of altering (increasing or decreasing) the expression level of genes important in the pathology of bone diseases, such as genes involved in inflammation, in vitro or in vivo. Among "inflammation-related genes," genes whose expression levels are reduced by the pharmaceutical composition of the present invention include, for example, angiogenesis-related factors (Ang, Serpinb2, etc.), cytokines (Il-1β, Tnfsf15, etc.), and chemokines (Ccl7, Cxcl2, etc.). For example, the expression level of Ang is significantly reduced by the combined use of the first and second components compared to the use of the first component (GPR40 agonist) alone or the second component (free fatty acid, an endogenous ligand of GPR40) alone.

[0175] In one aspect of the present invention, the pharmaceutical composition of the present invention has the effect of altering (increasing or decreasing) the expression levels of genes involved in pathways associated with bone metabolism and / or inflammation in vitro or in vivo. Examples of "pathways associated with bone metabolism and / or inflammation" include (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, and (R) TNF signaling.Furthermore, genes included in these pathways, particularly those whose expression levels do not change with the first component (GPR40 agonist) alone or the second component (free fatty acid, an endogenous ligand of GPR40) alone, but whose expression levels change with the combined use of the first and second components, include, for example, AAAS (increased), BCL2L1 (decreased), C3AR1 (decreased), CCL2 (decreased), CCL3 (decreased), CCL4 (decreased), CD36 (decreased), CSF1R (increased), CSF3 (decreased), DUSP5 (decreased), EIF4B (increased), EIF4G2 (decreased), GBP7 (decreased), GRIN1 (increased), IL7R (decreased), IP6K2 (decreased), LY These include N (decreased), NF1 (increased), NOS2 (decreased), PIK3CD (increased), PIM1 (decreased), PIP5K1C (increased), PLAUR (decreased), PLEKHO2 (decreased), PPP2CA (decreased), PSMA6 (decreased), PSMAY (decreased), PSMC2 (decreased), PSMD13 (decreased), PYGB (increased), RASGRP3 (increased), SDCBP (decreased), SMPD1 (decreased), SUMO1 (decreased), TNF (decreased), TNFRSF1B (decreased), TNFSF8 (decreased), and TNRC6B (increased) (the numbers in parentheses above indicate whether the expression level increases or decreases when the two components are used together compared to when not treated).

[0176] The various genes exemplified above can also be used, for example, as biomarkers related to the applications of the pharmaceutical composition of the present invention (patient stratification, diagnostic agents, diagnostic kits, PD markers for measuring effects in clinical trials, etc.).

[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, the contents of the first and second components in the pharmaceutical composition and the daily dose can be adjusted taking into account each of the above aspects, for example, the concentrations in the medium.

[0178] The pharmaceutical composition of the present invention contains at least a first ingredient and a second ingredient, and may further contain other active ingredients as needed, and these ingredients 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 any of (i) one in which the active ingredients are simultaneously administered using a single formulation and the same administration route, (ii) one in which the active ingredients are simultaneously administered using multiple formulations and the same administration route, (iii) one in which the active ingredients are administered using multiple formulations and the same administration route at different times, (iv) one in which the active ingredients are simultaneously administered using multiple formulations and multiple administration routes, or (v) one in which the active ingredients are administered using multiple formulations and multiple administration routes at different times.

[0179] -Method and Use- The method of the present invention for preventing or treating bone diseases in mammals comprises 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.

[0180] The use of a GPR40 agonist and a free fatty acid that is an endogenous ligand of GPR40 according to the present invention is for producing 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 to the above-mentioned method and use according to the present invention.

[0182] The pharmaceutical composition, method, and use of the present invention can be further converted into other aspects of the invention based on the description herein. For example, in one aspect, the present invention provides a method for suppressing differentiation into osteoclasts and / or a method for promoting differentiation into osteoblasts, using a GPR40 agonist and a free fatty acid that is an endogenous ligand of GPR40 (e.g., comprising a step of contacting the GPR40 agonist with cells in vivo or in vitro). [Example]

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

[0184] [Test Example 1] Inhibitory effect of mouse macrophage-derived cells on osteoclast differentiation Osteoclast differentiation is induced when osteoclast precursor cells are stimulated by RANKL (receptor activation of nuclear factor-kB ligand), which is produced by osteoblasts, etc. We investigated the inhibitory effect of compounds on osteoclast differentiation in macrophage cells, which are osteoclast precursor cells, when treated in the presence of RANKL.

[0185] R264.7 cells purchased from KAC were used for the study. Cells were suspended in DMEM containing 10% serum and seeded at 6000 cells / well in a 96-well plate. They were then cultured at 37°C under 5% CO2. After overnight culture, the medium was replaced with differentiation medium (DMEM containing 50 ng / mL RANKL and 10% serum) and 10 μM free fatty acids and 10 μM Fasiglifamin were added, either alone or in combination. γ-linolenic acid (SIGMA) or docosahexaenoic acid (SIGMA) were used as free fatty acids. Medium was replaced and compounds were added every other day. On day 3 of culture in differentiation medium, the medium was removed, and cell lysis solution (buffer RLT, RNeasy, QIAGEN) was added and mixed for 5 minutes. Samples for PCR were then collected. RNA was extracted from each sample using the RNeasy 96 kit (QIAGEN), and total RNA was obtained after DNase treatment. The resulting total RNA was reverse transcribed to cDNA using SuperScript IV (Thermo Fisher), and 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 TaqMan Gene Expression Assays (Applied Biosystems) were used for primers and probes complementary to each gene. The expression levels of each gene were normalized by the expression level of β-actin and expressed relative to the expression level of the RANKL-free control, which was set at 1.0. Some cells were cultured in differentiation medium for 5 days. On day 5, the cells were formalin-fixed and stained for tartrate-resistant acid phosphatase (TRAP), an osteoclast marker, to determine the proportion of osteoclasts.

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

[0187] [Test Example 2] Effect of combined use of compounds on LPS-stimulated mouse macrophage-derived cells The combined effects of compounds on changes in macrophage cells stimulated with bacterial lipopolysaccharide (LPS) were examined by comprehensive gene expression analysis using RNA next-generation sequencing.

[0188] [method] R264.7 cells purchased from KAC Co., Ltd. were used for the test. The cells were suspended in DMEM containing 10% serum and 1.6 × 10 5 Cells were seeded into 24-well plates at a concentration of 1000 cells / well and cultured at 37°C under 5% CO2. Thirty minutes before LPS addition, 10 μM free fatty acids and 10 μM Fasiglifem were added, either alone or in combination. Stearic acid was used as the free fatty acid. After 30 minutes of incubation following compound addition, LPS was added to each well at a concentration of 100 ng / mL. An equal volume of PBS was added to the unstimulated control group. After 24 hours of incubation with LPS, the medium was removed, and total RNA was extracted using RNeasy (QIAGEN). mRNA was recovered from the total RNA, libraries were prepared, and RNA sequencing (Illumina Hiseq) was performed. The following five groups of samples were sequenced, and the expression levels of each gene were estimated from the resulting read count data. After determining gene expression levels in each group, the expression levels in the control group (2) were compared with those in the compound-treated groups (3, 4, 5) to identify genes whose expression levels were significantly increased or decreased in the compound-treated groups (genes with altered expression levels). Furthermore, we performed pathway analysis of these differentially expressed genes and examined their association with disease. 1) Control 2) LPS 3) LPS+free fatty acids 4) LPS + Fasiglifam 5) LPS+Free fatty acids+Fasiglifam

[0189] [result] A comparison of the LPS group (2) and the compound-treated groups (3)–(5) revealed 572 genes with altered expression levels. Among these, genes related to angiogenesis (e.g., Ang, Serpinb2), cytokines (e.g., Il-1β, Tnfsf15), and chemokines (e.g., Ccl7, Cxcl2) were significantly reduced in expression when free fatty acids or Fasiglifam were combined with the LPS group compared with treatment with either compound alone (Figure 3). Furthermore, pathway analysis of these genes revealed associations with 204 pathways, 18 of which (Table 1) suggested a strong relationship to bone metabolism and inflammation. Some of the altered expression genes in these 18 pathways were not altered by treatment with free fatty acids or Fasiglifam alone, but were altered only by the combination of free fatty acids and Fasiglifam (Table 2). These results suggest that the combination of free fatty acids and Fasiglifam induces alterations in bone- and inflammation-related genes that are not observed with treatment with either compound alone.

[0190] [Table 1]

[0191] [Table 2]

Claims

1. A pharmaceutical composition for preventing or treating a bone disease, comprising a GPR40 agonist and a free fatty acid that is an endogenous ligand of GPR40, The GPR40 agonist is a compound represented by the following formula or a salt thereof, or a prodrug of a compound represented by the following formula: 【Chemical 1】 the free fatty acid that is an endogenous ligand of GPR40 is γ-linolenic acid and / or stearic acid; The prodrug is a compound in which the carboxy group in the above formula is esterified or amidated, The pharmaceutical composition is for use in treating a rare or intractable bone disease caused by increased osteoclast activity or formation and accompanied by inflammation, which has bone symptoms, pathological conditions of bone-related tissues, or pathological conditions of blood cells in bone or bone-related tissues.

2. A method for producing a pharmaceutical composition for preventing or treating a bone disease, comprising a step of mixing a GPR40 agonist and a free fatty acid, which is an endogenous ligand of GPR40, as active ingredients, The GPR40 agonist is a compound represented by the following formula or a salt thereof, or a prodrug of a compound represented by the following formula: 【Chemistry 2】 the free fatty acid that is an endogenous ligand of GPR40 is γ-linolenic acid and / or stearic acid; The prodrug is a compound in which the carboxy group in the above formula is esterified or amidated, A method for producing a pharmaceutical composition, wherein the bone disease is an intractable or rare bone disease caused by increased activity or formation of osteoclasts and accompanied by inflammation, and has bone symptoms in bone or bone-related tissues, or pathological conditions of bone-related tissues, or pathological conditions of blood cells.

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