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WO2015046317A1 - Novel acethylene amide derivative - Google Patents

Novel acethylene amide derivative Download PDF

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Publication number
WO2015046317A1
WO2015046317A1 PCT/JP2014/075403 JP2014075403W WO2015046317A1 WO 2015046317 A1 WO2015046317 A1 WO 2015046317A1 JP 2014075403 W JP2014075403 W JP 2014075403W WO 2015046317 A1 WO2015046317 A1 WO 2015046317A1
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group
pparγ
compound
thienyl
pyrimidin
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PCT/JP2014/075403
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French (fr)
Japanese (ja)
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宮地弘幸
大橋雅生
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国立大学法人岡山大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P17/00—Drugs for dermatological disorders
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/77—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/78—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/50—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to a novel acetylenamide derivative and an antagonist to peroxisome proliferator-activated receptors (PPAR) ⁇ , ⁇ / ⁇ , ⁇ . Specifically, the present invention relates to antagonists for all of PPAR ⁇ , ⁇ / ⁇ , and ⁇ , and antagonists for PPAR ⁇ . Furthermore, the present invention relates to a medicament or pharmaceutical composition for the treatment and / or prevention of diseases and the like caused by abnormal (enhanced) activity of PPAR ⁇ , ⁇ / ⁇ or ⁇ , and PPAR ⁇ , ⁇ / ⁇ or ⁇ activity. The present invention relates to a method for treating and / or preventing a disease caused by an abnormality (enhancement).
  • PPAR peroxisome proliferator-activated receptors
  • Peroxisome proliferator-activated receptor is a ligand-dependent transcription factor belonging to the nuclear receptor superfamily and induces transcription of target genes in a ligand-dependent manner. To do. That is, when a ligand binds to PPAR, PPAR binds to a PPAR responsive element (PPRE) present in the promoter region of the target gene, and transcription of the target gene is induced. In the cell, PPAR forms a heterodimer with the retinoid X receptor (RXR). This heterodimer binds to a DNA sequence known as the PPAR response element (PPRE) and activates transcription of various genes.
  • PPRE PPAR responsive element
  • the PPAR / RXR heterodimer incorporates activation cofactors such as DRIP-205 and SRC-1 to regulate the expression level of mRNA encoded by the target gene. So far, three types of subtypes ( ⁇ type, ⁇ / ⁇ type, ⁇ type) with different tissue distributions have been identified in various animal species including humans.
  • PPAR ⁇ is distributed in the liver, kidney, heart, muscle and the like where fatty acid catabolism is high, and is particularly expressed in the liver.
  • a decrease in neutral fat, an increase in HDL cholesterol, a decrease in body weight, promotion of angiogenesis, etc. are induced.
  • PPAR ⁇ antagonists have also been confirmed to have pharmaceutical effects. For example, Aboud et al. Have reported that GW6471, a PPAR ⁇ -specific antagonist, induces apoptosis of renal cell carcinoma-derived cell lines 786-O cells and Caki-1 cells.
  • Non-patent Document 1 It is expected to be effective as a therapeutic drug for cancer including the above (Non-patent Document 1). Furthermore, it has been shown that PPAR ⁇ antagonists inhibit the replication of HCV virus, and an effect as a therapeutic agent for HCV virus infection has been shown (Non-patent Document 2).
  • Non-Patent Document 3 Non-Patent Document 4
  • an antagonist of PPAR ⁇ / ⁇ has been confirmed to inhibit RNA replication of HCV virus, and is expected as a therapeutic agent for hepatitis C (Non-patent Document 5).
  • Non-patent Document 6 a selective antagonist of PPAR ⁇ / ⁇ is effective for the treatment of psoriasis, which is one of inflammatory skin diseases developed in mice.
  • SR13904 a PPAR ⁇ / ⁇ antagonist, inhibits the growth and survival of various cancer cell lines including lung cancer, breast cancer and liver cancer (Non-patent Document 7).
  • PPAR ⁇ is highly expressed in adipocytes and macrophages and induces proteins involved in adipocyte differentiation and acquisition of insulin sensitivity.
  • isoforms at least three types of PPAR ⁇ 1, ⁇ 2 and ⁇ 3 have been confirmed, and these are considered to be expressed as a result of alternative splicing.
  • a PPAR ⁇ antagonist is effective as a diabetic drug or an anti-obesity drug (Non-Patent Documents 8 to 11).
  • Non-patent Documents 12 and 13 suppression of the function of PPAR ⁇ induces the development of bone tissue
  • the PPAR ⁇ antagonist BADGE promotes differentiation into osteoblasts and increases bone mass in mice.
  • Non-Patent Document 14 and the like have been found, and PPAR ⁇ antagonists function in the formation of bone tissue and have been shown to be effective as therapeutic agents for osteoporosis, for example.
  • the expression of PPAR ⁇ has been confirmed in many cancer cells such as colorectal cancer, breast cancer, prostate cancer, pancreatic cancer, lung cancer, myeloid leukemia cells and lymphoid leukemia cells (Non-Patent Documents 15 to 17). ). Tsukahara et al.
  • Non-patent Document 18 cyclic phosphatidic acid, a PPAR ⁇ antagonist, suppresses the growth of colon cancer cells
  • Zaytseva et al It has been reported that cell proliferation is suppressed
  • Non-patent Document 19 Schaefer et al.
  • T0070907 a PPAR ⁇ antagonist, induces anoikis in liver cancer cells and exhibits antitumor activity
  • Non-patent Document 20 PPAR ⁇ antagonists have been shown to be effective against various cancers as anticancer agents.
  • fibrates such as fenofibrate, bezafibrate and clofibrate are already known as exogenous ligands for PPAR ⁇
  • thiazolidine-based agents such as troglitazone and pioglitazone are known as exogenous ligands for PPAR ⁇ .
  • Some substituted phenylpropionic acid derivatives have been reported as compounds that target each PPAR isoform other than fibrates and thiazolidines (see Patent Documents 1 to 6).
  • An object of the present invention is to provide a novel acetylenamide derivative, a compound having antagonist activity against all of PPAR ⁇ , PPAR ⁇ / ⁇ and PPAR ⁇ , and a compound having antagonist activity against PPAR ⁇ .
  • Another object of the present invention is to provide a transcriptional activity inhibitor for all of PPAR ⁇ , PPAR ⁇ / ⁇ , and PPAR ⁇ , and a transcriptional activity inhibitor for PPAR ⁇ , which contain the novel acetylenamide derivative as an active ingredient.
  • the present invention relates to a disease caused by abnormal (enhanced) transcriptional activity of PPAR ⁇ , PPAR ⁇ / ⁇ , and / or PPAR ⁇ containing the novel acetylenamide derivative as an active ingredient (for example, cancer that has developed in various tissues, Inflammatory skin diseases, diabetes, obesity, etc.) or therapeutic and / or prophylactic agent for diseases caused by infection with HCV virus that is thought to involve PPAR ⁇ , PPAR ⁇ / ⁇ , and / or PPAR ⁇
  • a disease caused by abnormal (enhanced) transcriptional activity of PPAR ⁇ , PPAR ⁇ / ⁇ , and / or PPAR ⁇ containing the novel acetylenamide derivative as an active ingredient (for example, cancer that has developed in various tissues, Inflammatory skin diseases, diabetes, obesity, etc.) or therapeutic and / or prophylactic agent for diseases caused by infection with HCV virus that is thought to involve PPAR ⁇ , PPAR ⁇ / ⁇ , and / or
  • the present invention relates to diseases caused by abnormal (enhanced) transcriptional activity of PPAR ⁇ , PPAR ⁇ / ⁇ , and / or PPAR ⁇ (eg, cancer that has developed in various tissues, inflammatory skin diseases, diabetes, obesity, etc.), or , PPAR ⁇ , PPAR ⁇ / ⁇ , and / or PPAR ⁇ , a method for treating or preventing a disease caused by infection with HCV virus, which is considered to be involved.
  • diseases caused by abnormal (enhanced) transcriptional activity of PPAR ⁇ , PPAR ⁇ / ⁇ , and / or PPAR ⁇ eg, cancer that has developed in various tissues, inflammatory skin diseases, diabetes, obesity, etc.
  • PPAR ⁇ , PPAR ⁇ / ⁇ , and / or PPAR ⁇ a method for treating or preventing a disease caused by infection with HCV virus, which is considered to be involved.
  • the present inventors have conducted extensive research and synthesized a novel acetylenamide derivative, which is a compound having an antagonist activity against all of PPAR ⁇ , PPAR ⁇ / ⁇ , and PPAR ⁇ , A compound having antagonist activity against PPAR has been found and the present invention has been completed.
  • the present invention relates to the general formula (I): [Wherein R 1 is unsubstituted or optionally substituted phenyl, pyrimidin-2-yl, 2-pyridyl, 2-thienyl, piperidino, cyclohexyl, adamantyl, trifluoromethyl A methoxy group, a phenoxy group, a 4-fluorophenoxy group, an anilino group, R 2 represents a hydrogen atom or a fluorine atom, R 3 represents a linear or branched alkyl group having 1 to 6 carbon atoms, R 4 represents an unsubstituted or optionally substituted phenyl group, a cycloalkyl group having 5 to 7 carbon atoms, a pyridyl group, a thienyl group], or a pharmaceutically acceptable salt thereof. Or a hydrate thereof, and a process for producing the acetylenamide derivative.
  • the present invention is a novel acetylenamide derivative represented by the above general formula (I), an antagonist that suppresses all transcription activities of PPAR ⁇ , PPAR ⁇ / ⁇ , and PPAR ⁇ , and an antagonist to PPAR ⁇ that suppresses the transcription activity of PPAR ⁇ . It is.
  • the present invention is a novel acetylenamide derivative represented by the above general formula (I), which is a transcription activity inhibitor for all of PPAR ⁇ , PPAR ⁇ / ⁇ , and PPAR ⁇ , and a transcription activity inhibitor for PPAR ⁇ .
  • the present invention is a pharmaceutical or a pharmaceutical composition containing the novel acetylenamide derivative represented by the above general formula (I) or a pharmaceutically acceptable salt or hydrate thereof.
  • this invention is a compound of the following general formula (II) suitable for manufacture of the compound represented by the said general formula (I).
  • R 1 is unsubstituted or optionally substituted phenyl, pyrimidin-2-yl, 2-pyridyl, 2-thienyl, piperidino, cyclohexyl, adamantyl, trifluoromethyl A methoxy group, a phenoxy group, a 4-fluorophenoxy group, an anilino group
  • R 2 represents a hydrogen atom or a fluorine atom
  • R 3 represents a linear or branched alkyl group having 1 to 6 carbon atoms
  • the present invention is a method for producing a compound represented by the above formula (I) using the compound represented by the above formula (II) as an intermediate.
  • a novel acetylenamide derivative and the novel acetylenamide derivative which are antagonists for all of PPAR ⁇ , PPAR ⁇ / ⁇ , and PPAR ⁇ , and antagonists for PPAR ⁇ .
  • the present invention also provides a transcriptional activity inhibitor for all of PPAR ⁇ , PPAR ⁇ / ⁇ , and PPAR ⁇ , and a transcriptional activity inhibitor for PPAR ⁇ .
  • diseases caused by abnormal transcription activity of PPAR ⁇ , PPAR ⁇ / ⁇ , or PPAR ⁇ such as cancer (kidney cancer, lung cancer, breast cancer, liver cancer, colon cancer, colon cancer, prostate cancer, pancreas, etc.
  • the compound represented by the general formula (I) of the present invention can be rapidly and efficiently produced by using the intermediate compound of the general formula (II).
  • the comparison of the action mechanism of the PPAR ⁇ antagonist of the present invention and the existing PPAR ⁇ antagonist is shown.
  • DMSO, pioglitazone, GW9662, Compound 1, Compound 12 and Compound 13 of the present invention were added to the assay system, and luciferase activity was measured.
  • the vertical axis represents the relative value of the emission intensity when the emission intensity when DMSO is added is 1.
  • the comparison of the action mechanism of the PPAR ⁇ antagonist of the present invention and the existing PPAR ⁇ antagonist is shown.
  • DMSO, pioglitazone, GW9662, Compound 1, Compound 12 and Compound 13 of the present invention were added to the assay system, and luciferase activity was measured.
  • the vertical axis represents the relative value of the emission intensity when the emission intensity when DMSO is added is 1.
  • A is the result of observing the state of differentiation into adipocytes when 10 nM, 100 nM, 1 ⁇ M and 10 ⁇ M compound 12 was added. The portion stained in red (dark color in the figure) is differentiated adipocytes.
  • B is the result of observing differentiation into adipocytes when Compound 12 is added in the presence of pioglitazone, which is a PPAR ⁇ agonist. The upper side of B is the result of adding only pioglitazone, and the lower side is the result of adding pioglitazone and Compound 12.
  • pio Pioglitazone
  • Chemical formula 12 Compound 12
  • the result of having investigated the influence on the adipocyte differentiation of the compound of this invention is shown. It is the result of observing differentiation into adipocytes when compound 13 is added in the presence of pioglitazone which is a PPAR ⁇ agonist. The absorbance at 490 mn is shown on the vertical axis. In the presence of 1 ⁇ M pioglitazone, 1 ⁇ M and 10 ⁇ M of Compound 13 were added to confirm the effect. The result of having compared the inhibitory effect on the adipocyte differentiation of the PPAR ⁇ antagonist of the present invention and the existing PPAR ⁇ antagonist is shown.
  • One of the embodiments of the present invention is a novel acetylenamide derivative represented by the general formula (I) or a pharmaceutically acceptable salt or hydrate thereof, or the novel acetylenamide derivative, wherein PPAR ⁇ , PPAR ⁇ / ⁇ , antagonist to all of PPAR ⁇ , antagonist to PPAR ⁇ .
  • the “antagonist” is a compound that interacts with PPAR ⁇ , PPAR ⁇ / ⁇ , and / or PPAR ⁇ to suppress transcriptional activation of a target gene by PPAR ⁇ , PPAR ⁇ / ⁇ , or PPAR ⁇ .
  • R 1 is an unsubstituted or optionally substituted phenyl group, pyrimidin-2-yl group, 2-pyridyl group, 2-thienyl group, piperidino group, cyclohexyl group, adamantyl group , A trifluoromethyl group, a methoxy group, a phenoxy group, a 4-fluorophenoxy group, and an anilino group, preferably a pyrimidin-2-yl group, an adamantyl group, and a 4-fluorophenoxy group.
  • R 2 represents a hydrogen atom or a fluorine atom, preferably a hydrogen atom.
  • R 3 represents a linear or branched alkyl group having 1 to 6 carbon atoms, preferably a linear alkyl group having 1 to 5 carbon atoms.
  • R 4 is an unsubstituted or optionally substituted phenyl group (for example, phenyl group, 2-methylphenyl group, 3-methylphenyl group, 2-methoxyphenyl group, 4-methoxyphenyl group, 2-fluorophenyl).
  • the compound of the present invention represented by the general formula (I) may be not only a novel acetylenamide derivative represented by the general formula (I) but also a salt thereof or a solvate or hydrate thereof.
  • the salt of the novel acetylenamide derivative is not particularly limited, and is a conventional salt, for example, an alkali metal salt such as sodium salt, potassium salt or lithium salt; an alkaline earth metal salt such as calcium salt or magnesium salt; aluminum salt And the like, and preferably pharmaceutically acceptable.
  • novel acetylenamide derivatives represented by the general formula (I) include stereoisomers such as tautomers and enantiomers thereof unless otherwise specified. That is, when one or more asymmetric carbons are contained in the novel acetylenamide derivative represented by the general formula (I), the stereochemistry of the asymmetric carbons is independently (R) isomer. Alternatively, it can take either (S) form and may exist as a stereoisomer such as an enantiomer or diastereomer of the derivative. As an active ingredient of the medicament of the present invention described later, it is possible to use any stereoisomer in a pure form, any mixture of stereoisomers, racemate and the like.
  • Another embodiment of the present invention is a compound represented by the general formula (I I).
  • the compound represented by the general formula (II) is an intermediate compound suitable for producing a novel acetylenamide derivative of the general formula (I).
  • the compound of the general formula (I) is a compound represented by the general formula (II) and a compound represented by the following formula (VIII) It can be synthesized by a condensation reaction of Through such a synthesis process, the compound of the general formula (I) can be synthesized quickly and easily.
  • R 1 is an unsubstituted or optionally substituted phenyl group, pyrimidin-2-yl group, 2-pyridyl group, 2-thienyl group, piperidino group, cyclohexyl group, adamantyl group , A trifluoromethyl group, a methoxy group, a phenoxy group, a 4-fluorophenoxy group, and an anilino group, preferably a pyrimidin-2-yl group, an adamantyl group, and a 4-fluorophenoxy group.
  • R 2 represents a hydrogen atom or a fluorine atom, preferably a hydrogen atom.
  • R 3 represents a linear or branched alkyl group having 1 to 6 carbon atoms, preferably a linear alkyl group having 1 to 5 carbon atoms.
  • the antagonists and salts thereof selective for PPAR ⁇ represented by the general formula (I) include, but are not limited to, the following.
  • N- (5- (3-phenylpropiolamido) -2-propoxybenzyl) -4- (pyrimidin-2-yl) benzamide N- (5- (3-phenylpropiolamido) -2-propoxybenzyl) -4- (pyrimidin-2-yl) benzamide]
  • N- (2-propoxy-5- (3-o-toluylpropiolamido) benzyl) -4- (pyrimidin-2-yl) benzamide N- (5- (3- (2-chlorophenyl) propiolamido) -2-propoxybenzyl) -4- (pyrimidin-2-yl) benzamide
  • R 1 is a pyrimidin-2-yl group
  • R 2 is a hydrogen atom
  • R 3 is a linear alkyl group having 3 carbon atoms
  • R 4 Is an unsubstituted or optionally substituted phenyl group, a cycloalkyl group having 5 to 7 carbon atoms
  • a compound (Ia) represented by a pyridyl group can be produced by the following method (Scheme 1) .
  • R 3 represents a linear or branched alkyl group having 1 to 6 carbon atoms
  • R 4 represents a phenyl group which may be unsubstituted or substituted, or a cycloalkyl group having 5 to 7 carbon atoms.
  • Represents a pyridyl group the compound represented by the following:
  • step c [Wherein R 3 is as defined above] and can be produced by condensing the compound (V) and 4- (pyrimidin-2-yl) benzoic acid (step c) as follows: [Wherein R 3 has the same meaning as described above] and can be produced by reducing (step d) the following compound (VI): [Wherein R 3 has the same meaning as defined above] and the following intermediate (IIa): It can be synthesized by condensing with a compound represented by the compound (VIII) represented by [wherein R 4 has the same meaning as described above] (step e).
  • step a is carried out in a solvent such as tetrahydrofuran, diethyl ether, DMF or DMSO as a base, for example, an alkali metal hydride such as sodium hydride, an organometallic compound such as butyl lithium, lithium diisopropylamide, sodium bis ( Metal amides such as trimethylsilyl) amide can be used.
  • a solvent such as tetrahydrofuran, diethyl ether, DMF or DMSO
  • an alkali metal hydride such as sodium hydride
  • an organometallic compound such as butyl lithium, lithium diisopropylamide, sodium bis ( Metal amides such as trimethylsilyl) amide
  • the reaction can be performed at -100 ° C to 150 ° C, preferably -80 ° C to 100 ° C.
  • the reaction time is usually 1 to 48 hours, preferably 2 to 24 hours.
  • the reaction in step b can be carried out in a solvent such as toluene, acetonitrile, ethyl acetate, N, N-dimethylformamide in the presence of triethylsilane.
  • the reaction temperature can be 0 to 150 ° C., preferably room temperature to 100 ° C.
  • the reaction time is usually 0.5 to 24 hours, preferably 1 to 5 hours.
  • the reaction in step c may be carried out in a solvent such as tetrahydrofuran, diethyl ether, dichloromethane, chloroform, hexane, or DMF in the presence of a condensing agent and in the presence or absence of triethylamine, diisopropylethylamine, pyridine, or lutidine as a base. it can.
  • the reaction can be carried out at ⁇ 50 to 100 ° C., preferably ⁇ 20 to 50 ° C.
  • the reaction time is usually 1 to 48 hours, preferably 6 to 24 hours.
  • the reaction in step d is carried out in the presence of a metal catalyst such as palladium-supported activated carbon, platinum-supported activated carbon, platinum oxide, and rhodium-supported alumina in a solvent such as ethanol, methanol, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, and a hydrogen pressure of 98. It can be carried out at 1 kPa to 491 kPa.
  • the reaction temperature can be 0 to 150 ° C., preferably room temperature to 100 ° C.
  • the reaction time is usually 0.5 to 24 hours, preferably 1 to 5 hours.
  • the reaction in step e may be performed in a solvent such as tetrahydrofuran, diethyl ether, dichloromethane, chloroform, hexane, or DMF, in the presence of a condensing agent, and in the presence or absence of triethylamine, diisopropylethylamine, pyridine, or lutidine as a base. it can.
  • the reaction can be carried out at ⁇ 50 to 100 ° C., preferably ⁇ 20 to 50 ° C.
  • the reaction time is usually 1 to 48 hours, preferably 6 to 24 hours.
  • a transcriptional activity inhibitor for all of PPAR ⁇ , PPAR ⁇ / ⁇ , and PPAR ⁇ containing a novel acetylenamide derivative represented by the general formula (I) (a drug that suppresses transcription of PPAR ⁇ , PPAR ⁇ / ⁇ , PPAR ⁇ target genes)
  • a transcriptional activity inhibitor for PPAR ⁇ a transcriptional activity inhibitor for PPAR ⁇ .
  • the present invention also relates to a medicament or pharmaceutical composition comprising a novel acetylenamide derivative represented by the general formula (I) of the present invention, which is an antagonist to all of PPAR ⁇ , PPAR ⁇ / ⁇ and PPAR ⁇ , and a compound which is an antagonist to PPAR ⁇ . Included in the range.
  • the medicament of the present invention can be used as a therapeutic or prophylactic agent for PPAR ⁇ , PPAR ⁇ / ⁇ , and / or PPAR ⁇ dysfunction, in particular, a disease or the like that develops due to excessive enhancement of its activity, and PPAR ⁇ , PPAR ⁇ / ⁇ , And / or can be used as a therapeutic or prophylactic agent for a disease (referred to as HCV virus infection) caused by infection with HCV virus, which is thought to involve PPAR ⁇ .
  • HCV virus infection a disease caused by infection with HCV virus
  • Non-patent Document 1 it has been reported that GW6471, a PPAR ⁇ -specific antagonist, induces apoptosis of renal cell carcinoma-derived cell lines, and PPAR ⁇ antagonists can be used as therapeutic agents for cancers including kidney cancer and the like. It has also been reported that PPAR ⁇ antagonists inhibit HCV virus replication and can be used as therapeutic agents for HCV virus infection (Non-patent Document 2).
  • PPAR ⁇ / ⁇ antagonists have been reported to exhibit HCV RNA replication inhibitory activity and can be used as therapeutic agents for hepatitis C (Non-patent Document 5). Furthermore, since selective antagonists of PPAR ⁇ / ⁇ have been reported to be effective in the treatment of psoriasis, which is one of inflammatory skin diseases, they can also be used as therapeutic agents for inflammatory skin diseases (non- Patent Document 6). In addition, the PPAR ⁇ / ⁇ antagonist SR13904 has been reported to inhibit the growth and survival of various cancer cell lines, including lung cancer, breast cancer and liver cancer, and can also be used as an anticancer agent (non-cancerous) Patent Document 7).
  • Non-Patent Documents 8 to 11 it is disclosed that PPAR ⁇ antagonists are effective as antidiabetic drugs or anti-obesity drugs (Non-Patent Documents 8 to 11). Moreover, suppression of the function of PPAR ⁇ induces the development of bone tissue (Non-patent Documents 12 and 13), and the PPAR ⁇ antagonist BADGE promotes differentiation into osteoblasts and increases bone mass in mice. (Non-Patent Document 14) and the like have been found, and PPAR ⁇ antagonists function in the formation of bone tissue and are effective as therapeutic agents for osteoporosis, for example.
  • Non-Patent Documents 15 to 17 Tsukahara et al. Have reported that cyclic phosphatidic acid, a PPAR ⁇ antagonist, suppresses the growth of colon cancer cells (Non-patent Document 18), and Zaytseva et al. It has been reported that cell proliferation is suppressed (Non-patent Document 19). Schaefer et al.
  • Non-patent Document 20 PPAR ⁇ antagonists
  • novel acetylenamide derivatives represented by the formula (I) of the present invention are cancers of various tissues, diabetes, obesity, hyperlipidemia, hypertension, arteriosclerosis, hypercholesterolemia, HCV virus infection It can be used as an active ingredient of a therapeutic or prophylactic agent for inflammatory skin diseases (such as psoriasis) and diseases caused by poor bone tissue formation.
  • a physiologically acceptable salt thereof may be used in addition to the compound represented by the above general formula (I).
  • the salt include alkali metal and alkaline earth metal salts such as lithium, sodium, potassium, magnesium, and calcium; ammonia, methylamine, dimethylamine, trimethylamine, dicyclohexylamine, tris ( A salt of an amine such as hydroxymethyl) aminomethane, N, N-bis (hydroxyethyl) piperazine, 2-amino-2-methyl-1-propanol, ethanolamine, N-methylglucamine, L-glucamine; or lysine; Salts with basic amino acids such as ⁇ -hydroxylysine and arginine can be formed.
  • salts of mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; methanesulfonic acid, benzenesulfonic acid, paratoluenesulfonic acid, acetic acid, propionate, tartaric acid , Fumaric acid, maleic acid, malic acid, oxalic acid, succinic acid, citric acid, benzoic acid, mandelic acid, cinnamic acid, lactic acid, glycolic acid, glucuronic acid, ascorbic acid, nicotinic acid, salicylic acid and other organic acids Salts; or salts with acidic amino acids such as aspartic acid and glutamic acid.
  • a solvate or hydrate of the compound represented by the general formula (I) or a salt thereof can be used as the active ingredient of the medicament of the present invention.
  • the medicament of the present invention may be administered with an active ingredient compound represented by the general formula (I) and a pharmacologically acceptable salt thereof, or a solvate thereof or a hydrate thereof.
  • an active ingredient of the medicament of the present invention two or more of the above substances can be used in combination, and the above pharmaceutical composition includes cancer, diabetes, hyperlipidemia, hypercholesterolemia, hypertension, obesity. It is also possible to incorporate other known active ingredients for the prevention or treatment of various symptoms such as arteriosclerosis, inflammatory skin disease, osteoporosis, or the prevention or treatment of HCV virus infection.
  • the type of the pharmaceutical composition of the present invention is not particularly limited, and dosage forms include tablets, capsules, granules, powders, syrups, suspensions, suppositories, ointments, creams, gels, patches, Examples include inhalants and injections. These preparations are prepared according to a conventional method.
  • the pharmaceutical composition of the present invention includes intravenous, intradermal, subcutaneous, oral (including inhalation and the like), transdermal and transmucosal administration, and is adapted to a therapeutically appropriate route of administration. Formulated.
  • Solutions or suspensions used for parenteral, intradermal, or subcutaneous application include, but are not limited to, sterile diluents such as water for injection, saline solutions, non-volatile oils, polyethylene glycols, Glycerin, propylene glycol, or other synthetic solvents, benzyl alcohol or other preservatives such as methylparaben, antioxidants such as ascorbic acid or sodium bisulfite, soothing agents such as benzalkonium chloride, procaine hydrochloride, ethylenediaminetetraacetic acid A chelating agent such as (EDTA), a buffering agent such as acetate, citrate, or phosphate, and a drug for osmotic pressure adjustment such as sodium chloride or dextrose may be included.
  • sterile diluents such as water for injection, saline solutions, non-volatile oils, polyethylene glycols, Glycerin, propylene glycol, or other synthetic solvents
  • Liquid preparations may be dissolved or suspended in water or other suitable solvent when used. Tablets and granules may be coated by a known method. In the case of injection, it is prepared by dissolving the compound of the present invention in water, but it may be dissolved in physiological saline or glucose solution as necessary, and a buffer or preservative may be added. Good. It is provided in any dosage form for oral or parenteral administration.
  • a pharmaceutical composition for oral administration in the form of granules, fine granules, powders, hard capsules, soft capsules, syrups, emulsions, suspensions or liquids, for intravenous administration, for intramuscular administration
  • it can be prepared as a pharmaceutical composition for parenteral administration in the form of injections, drops, transdermal absorbents, transmucosal absorbents, nasal drops, inhalants, suppositories, etc. for subcutaneous administration.
  • Injections, infusions, and the like can be prepared as powdered dosage forms such as freeze-dried forms, and can be used by dissolving in an appropriate aqueous medium such as physiological saline at the time of use. It is also possible to administer a sustained release preparation coated with a polymer directly into the brain.
  • a person skilled in the art can appropriately select the type of pharmaceutical additive used for the production of the pharmaceutical composition, the ratio of the pharmaceutical additive to the active ingredient, or the method for producing the pharmaceutical composition depending on the form of the composition. It is.
  • an inorganic or organic substance, or a solid or liquid substance can be used, and generally it can be blended in an amount of 1 to 90% by weight based on the weight of the active ingredient.
  • examples of such substances are lactose, glucose, mannitol, dextrin, cyclodextrin, starch, sucrose, magnesium aluminate metasilicate, synthetic aluminum silicate, sodium carboxymethylcellulose, hydroxypropyl starch, carboxymethylcellulose calcium.
  • an active ingredient and excipient components such as lactose, starch, crystalline cellulose, calcium lactate, anhydrous silicic acid and the like are mixed to form a powder, or if necessary, sucrose, Add a binder such as hydroxypropylcellulose and polyvinylpyrrolidone, a disintegrant such as carboxymethylcellulose and carboxymethylcellulose calcium, and wet or dry granulate to form granules.
  • these powders and granules may be tableted as they are or after adding a lubricant such as magnesium stearate or talc.
  • These granules or tablets may be coated with an enteric solvent base such as hydroxypropylmethylcellulose phthalate or methacrylic acid-methyl methacrylate polymer and coated with an enteric solvent preparation or ethylcellulose, carnauba wax, hardened oil, etc. to form a sustained preparation. it can.
  • an enteric solvent base such as hydroxypropylmethylcellulose phthalate or methacrylic acid-methyl methacrylate polymer
  • an enteric solvent preparation or ethylcellulose, carnauba wax, hardened oil, etc. to form a sustained preparation. it can.
  • powders or granules are filled into hard capsules, or active ingredients are dissolved as they are or dissolved in glycerin, polyethylene glycol, sesame oil, olive oil, etc., and then coated with a gelatin film to form soft capsules. Can do.
  • active ingredients such as hydrochloric acid, sodium hydroxide, lactose, lactic acid, sodium, sodium monohydrogen phosphate, sodium dihydrogen phosphate, etc. Dissolve in distilled water for injection together with an isotonic agent, filter aseptically and fill into ampoules, or add mannitol, dextrin, cyclodextrin, gelatin, etc. .
  • reticine, polysorbate 80, polyoxyethylene hydrogenated castor oil and the like can be added to the active ingredient and emulsified in water to give an emulsion for injection.
  • the active ingredient is moistened with a suppository base material such as cacao butter, fatty acid tri, di- and monoglycerides, polyethylene glycol, etc., dissolved, poured into a mold and cooled, or the active ingredient is made of polyethylene. What is necessary is just to coat
  • the dose and frequency of administration of the medicament of the present invention are not particularly limited, and conditions such as prevention and / or progression of the disease to be treated and / or purpose of treatment, type of disease, patient weight and age, severity of the disease, etc. Depending on the situation, it is possible to make an appropriate selection based on the judgment of the doctor.
  • the dose per day for an adult in oral administration is about 0.01 to 1000 mg (weight of active ingredient) and can be administered once or several times a day or every few days. it can.
  • daily dosages of 0.001 to 100 mg (active ingredient weight) are preferably administered continuously or intermittently to adults.
  • the medicament of the present invention can be prepared as a sustained-release preparation such as a delivery system encapsulated in implantable tablets and microcapsules, using a carrier that can prevent immediate removal from the body.
  • a carrier for example, biodegradable and biocompatible polymers such as ethylene vinyl acetate, polyanhydride, polyglycolic acid, collagen, polyorthoester, and polylactic acid can be used. Such materials can be readily prepared by those skilled in the art. Liposome suspensions can also be used as pharmaceutically acceptable carriers.
  • Useful liposomes are prepared as a lipid composition comprising, but not limited to, phosphatidylcholine, cholesterol and PEG-derivatized phosphatidylethanol (PEG-PE) through a filter of appropriate pore size so as to be suitable for use, and in reverse phase. Purified by evaporation.
  • PEG-PE PEG-derivatized phosphatidylethanol
  • the medicament of the present invention can be included as a pharmaceutical composition in the form of a kit together with instructions for administration in a container or pack.
  • a kit different components of the composition are packaged in separate containers and mixed immediately before use. The reason why the components are packaged separately in this way is to enable long-term storage without losing the function of the active component.
  • the reagent contained in the kit is supplied into a container made of a material that maintains the activity of the component effectively for a long period of time, does not adsorb inside the container, and does not alter the component.
  • a sealed glass ampoule may include a buffer sealed in the presence of a neutral and non-reactive gas such as nitrogen gas.
  • the ampoule is composed of glass, polycarbonate, organic polymers such as polystyrene, ceramic, metal, or any other suitable material commonly used to hold reagents.
  • instructions for use may be attached to the kit.
  • Instructions for use of this kit are printed on paper and / or on electrically or electromagnetically readable media such as floppy disks, CD-ROMs, DVD-ROMs, videotapes, audiotapes, etc. It may be stored and supplied to the user. Detailed instructions for use may be actually attached to the kit, or may be posted on a website designated by the manufacturer or distributor of the kit or notified by e-mail or the like.
  • the present invention includes diseases caused by abnormal (enhanced) transcriptional activity of PPAR ⁇ , PPAR ⁇ / ⁇ , and / or PPAR ⁇ (eg, cancer that has developed in various tissues, inflammatory skin diseases, hyperlipidemia, Hypercholesterolemia, hypertension, obesity, arteriosclerosis, diabetes mellitus, diseases that develop due to the imbalance of bone tissue formation and resorption such as bone tissue formation failure or bone resorption rate higher than bone formation rate (for example, , Osteoporosis, etc.), or a method for treating or preventing a disease caused by infection with an HCV virus that is thought to involve PPAR ⁇ , PPAR ⁇ / ⁇ , and / or PPAR ⁇ .
  • diseases caused by abnormal (enhanced) transcriptional activity of PPAR ⁇ , PPAR ⁇ / ⁇ , and / or PPAR ⁇ eg, cancer that has developed in various tissues, inflammatory skin diseases, hyperlipidemia, Hypercholesterolemia, hypertension, obesity, arteriosclerosis
  • treatment refers to preventing or alleviating the progression and worsening of the pathological condition in mammals suffering from diseases that develop due to abnormal PPAR ⁇ , PPAR ⁇ / ⁇ , and / or PPAR ⁇ transcriptional activity. It means a treatment aimed at preventing or alleviating the progression and worsening of the disease.
  • prevention refers to blocking in advance the onset or illness of a mammal that may be affected by a disease that develops due to abnormal PAR ⁇ , PPAR ⁇ / ⁇ , and / or PPAR ⁇ transcriptional activity. This is a treatment aimed at preliminarily preventing the onset of various symptoms of the disease.
  • the “mammal” to be treated means any animal classified as a mammal, and is not particularly limited.
  • pet animals such as dogs, cats, rabbits, cows, pigs, sheep , Livestock animals such as horses.
  • Particularly preferred “mammals” are humans.
  • N- (5-amino-2-propoxybenzyl) -4- (pyrimidin-2-yl) benzamide 500 mg (1.27 mmol) N- (5-nitro-2-propoxybenzyl) -4- (pyrimidin-2-yl) benzamide, 250 mg 10% palladium carbon, 100 ml ethyl acetate, 50 ml methanol Then, catalytic reduction was performed at a hydrogen pressure of 0.4 MPa. The palladium was removed by Celite filtration, and the filtrate was concentrated to obtain 455 mg (yield 98%) of the title compound.
  • N- (5- (3-Phenylpropiolamido) -2-propoxybenzyl) -4- (pyrimidin-2-yl) benzamide In a 50 ml eggplant-shaped flask, 50 mg (0.138 mmol) N- (5-amino-2-propoxybenzyl) -4- (pyrimidin-2-yl) benzamide, 24 mg (0.165 mmol) phenylpropiolic acid, 63 mg (0.165 mmol) O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate, 0.07 ml (0.414 mmol) DIEA, 10 ml N, N- Dimethylformamide was added and stirred overnight.
  • luciferase activity and ⁇ -galactosidase activity are measured 16 hours after addition of the test compound and TIPP-703 which is a PPAR pan agonist (compounds 1 to 16) or 24 hours (compounds 17 to 27). Corrected by the internal standard.
  • Table 7 shows the IC 50 values for PPAR ⁇ , PPAR ⁇ / ⁇ , and PPAR ⁇ measured by the above method. In the table, NT indicates not tested, and ND indicates not determined.
  • the compounds 1 to 16 of the present invention act as antagonists for PPAR ⁇ .
  • R 4 in formula (Ib) is a phenyl group, a compound having a substituent or the like at the 2-position thereof (compound 13, as well as compounds 2, 15, 16, etc.), and R 4 is pyrimidine-2 -Since the compound (compound 12) in which the 2-position of the benzene ring is nitrogen or the like as in the yl group has almost no agonist activity (data not shown), such a compound has a strong PPAR ⁇ Are considered to be selective antagonists.
  • Compounds 17 to 27 were confirmed to have antagonist activity against PPAR ⁇ , PPAR ⁇ / ⁇ and PPAR ⁇ .
  • Comparison of action mechanism of PPAR ⁇ antagonists of the present invention (compounds 1 to 16) and existing PPAR ⁇ antagonists 2-1. Comparison 1 It was examined whether there is a difference in the mechanism of action with the existing PPAR ⁇ antagonist GW9662. Specifically, in order to examine whether there is a difference in the effect of inactivating PPAR ⁇ , a comparison was made with respect to the efficacy of enhancing the interaction between PPAR ⁇ and the corepressor. In general, it is known that PPAR ⁇ has a higher inactivation effect as PPAR ⁇ and a corepressor interact (J Biol Chem. 2005 Apr 8; 280 (14): 13600-5.).
  • VP16 herpesvirus activation domain
  • COS-1 African green monkey kidney cells
  • FBS / DMEM Dulbecco's modified Eagle medium
  • a receptor plasmid expressing a fusion protein of a protein-expressing plasmid, a yeast transcription factor (GAL4) DNA-binding region and a human-type PPAR ⁇ ligand-binding region, and a reporter plasmid thereof, and a secreted alkaline phosphatase for an internal standard
  • the (SEAP) plasmid was co-transfected using X-tremegene9, a transfection reagent.
  • test compounds pioglitazone, GW9662, compound 12 and compound 13
  • luciferase activity and alkaline phosphatase activity were measured 24 hours later and corrected with an internal standard. The measurement results are shown in FIG.
  • test compounds pioglitazone, GW9662, compound 12 and compound 13
  • luciferase activity and alkaline phosphatase activity were measured 24 hours later and corrected with an internal standard. The measurement results are shown in FIG.
  • Day2 1 mL of DMSO or DMEM (10% FBS) containing each concentration of test compound was added to each well (medium addition).
  • Day3 The medium was changed in each well with 2 mL of DMSO or 10% FBS DMEM containing each concentration of test compound.
  • Day5 Same operation as Day3.
  • Day7 Same operation as Day3.
  • Day9 Oil red O staining (staining method for confirming differentiation from preadipocytes to adipocytes) was performed, and the stained cells were observed with a microscope. In cells differentiated into adipocytes, triglycerides in the cells are stained red by O staining. The stronger the red staining, the greater the degree of differentiation into adipocytes.
  • Pioglitazone an agonist of PPAR ⁇ , strongly induced differentiation into adipocytes (higher absorbance than control DMSO).
  • Compound 13 almost completely suppressed the induction of adipocytes by pioglitazone. That is, Compound 13 acted as a PPAR ⁇ full antagonist in preadipocytes, and strongly suppressed its differentiation into adipocytes.
  • the compounds 1 to 16 of the present invention have PPAR ⁇ antagonist activity, and in particular, the compounds 12 and 13 strongly suppress the induction of differentiation into adipocytes as compared with the existing GW9662. It became clear. Therefore, the compound of the present invention can be used as an active ingredient of a therapeutic agent for metabolic syndrome such as diabetes and obesity.
  • adipocytes and osteoblasts are differentiated from mesenchymal stem cells while maintaining the balance of their abundance, and further knowledge that PPAR ⁇ antagonists induce the development of bone tissue ( Non-patent document 13) suggests that the compounds of the present invention can also be used for the treatment of osteoporosis and the like.
  • the compound of the present invention has PPAR ⁇ , PPAR ⁇ / ⁇ , PPAR ⁇ antagonist activity. Therefore, a medicament containing these compounds as an active ingredient is expected to exert an effect on treatment of diseases caused by abnormal PPAR activity.

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Abstract

The purpose of the present invention is to provide novel acethylene amide derivatives, i.e., a compound having an antagonistic activity on all of PPARα, PPARβ/δ and PPARγ, a compound having an antagonistic activity on at least one subtype among PPARα, PPARβ/δ and PPARγ, and a compound capable of inhibiting a PPARγ-selective antagonistic activity. A compound provided by the present invention is an acethylene amide derivative represented by general formula (I).

Description

新規アセチレンアミド誘導体New acetylenamide derivatives
　本発明は、新規アセチレンアミド誘導体であって、ペルオキシソーム増殖薬活性化受容体（ＰＰＡＲ）α、β／δ、γに対するアンタゴニストに関する。具体的には、本発明は、ＰＰＡＲα、β／δ、γのすべてに対するアンタゴニスト、ＰＰＡＲγに対するアンタゴニストに関する。さらに、本発明は、ＰＰＡＲα、β／δ又はγの活性異常（亢進）に起因する疾患等の治療及び／又は予防のための医薬又は医薬組成物、並びに、ＰＰＡＲα、β／δ又はγ活性の異常（亢進）に起因する疾患等の治療及び／又は予防方法に関する。 The present invention relates to a novel acetylenamide derivative and an antagonist to peroxisome proliferator-activated receptors (PPAR) α, β / δ, γ. Specifically, the present invention relates to antagonists for all of PPARα, β / δ, and γ, and antagonists for PPARγ. Furthermore, the present invention relates to a medicament or pharmaceutical composition for the treatment and / or prevention of diseases and the like caused by abnormal (enhanced) activity of PPARα, β / δ or γ, and PPARα, β / δ or γ activity. The present invention relates to a method for treating and / or preventing a disease caused by an abnormality (enhancement).
　ペルオキシソーム増殖剤応答性受容体（Peroxisome proliferator-activated receptor：ＰＰＡＲ、以下ＰＰＡＲとする）は、核内受容体スーパーファミリーに属するリガンド依存性の転写因子であり、標的遺伝子の転写をリガンド依存的に誘導する。すなわち、リガンドがＰＰＡＲに結合すると、ＰＰＡＲは標的遺伝子のプロモーター領域に存在するＰＰＡＲ応答配列（PPAR responsive element：ＰＰＲＥ）に結合し、標的遺伝子の転写が誘導される。
　細胞内において、ＰＰＡＲはレチノイドＸレセプター（ＲＸＲ）とヘテロ二量体を形成する。このヘテロ二量体がＰＰＡＲ応答配列（ＰＰＲＥ）として知られるＤＮＡ配列に結合して、各種遺伝子の転写を活性化する。また、ＰＰＡＲ／ＲＸＲヘテロ二量体は、ＤＲＩＰ－２０５やＳＲＣ－１などの活性化補助因子を取り込んで、標的遺伝子にコードされるｍＲＮＡの発現レベルを調節する。これまでに組織分布を異にする３種類のサブタイプ（α型、β／δ型、γ型）がヒトをはじめとする様々な動物種で同定されている。 Peroxisome proliferator-activated receptor (PPAR) is a ligand-dependent transcription factor belonging to the nuclear receptor superfamily and induces transcription of target genes in a ligand-dependent manner. To do. That is, when a ligand binds to PPAR, PPAR binds to a PPAR responsive element (PPRE) present in the promoter region of the target gene, and transcription of the target gene is induced.
In the cell, PPAR forms a heterodimer with the retinoid X receptor (RXR). This heterodimer binds to a DNA sequence known as the PPAR response element (PPRE) and activates transcription of various genes. In addition, the PPAR / RXR heterodimer incorporates activation cofactors such as DRIP-205 and SRC-1 to regulate the expression level of mRNA encoded by the target gene. So far, three types of subtypes (α type, β / δ type, γ type) with different tissue distributions have been identified in various animal species including humans.
　これらのうち、ＰＰＡＲαは、脂肪酸の異化能の高い肝臓、腎臓、心臓及び筋肉等に分布しており、特に肝臓において高い発現が認められ、ＰＰＡＲαによって標的遺伝子の転写が誘導されると、血中中性脂肪の低下、ＨＤＬコレステロールの増加、体重の減少、血管新生の促進等が誘起される。これまでに、ＰＰＡＲαのアゴニストとして作用する種々の治療薬が報告されているが、ＰＰＡＲαのアンタゴニストについても、医薬としての効果が確認されている。例えば、Aboudらは、ＰＰＡＲα特異的なアンタゴニストであるGW6471が腎細胞癌由来の細胞株である786-O細胞及びCaki-1細胞のアポトーシスを誘導することを報告しており、ＰＰＡＲαアンタゴニストに腎臓癌などを含む癌の治療薬としての効果が期待されている（非特許文献１）。さらに、ＰＰＡＲαアンタゴニストがHCVウイルスの複製を阻害することが示されており、HCVウイルス感染症の治療薬としての効果が示されている（非特許文献２） Among these, PPARα is distributed in the liver, kidney, heart, muscle and the like where fatty acid catabolism is high, and is particularly expressed in the liver. When transcription of a target gene is induced by PPARα, A decrease in neutral fat, an increase in HDL cholesterol, a decrease in body weight, promotion of angiogenesis, etc. are induced. So far, various therapeutic agents that act as agonists of PPARα have been reported, but PPARα antagonists have also been confirmed to have pharmaceutical effects. For example, Aboud et al. Have reported that GW6471, a PPARα-specific antagonist, induces apoptosis of renal cell carcinoma-derived cell lines 786-O cells and Caki-1 cells. It is expected to be effective as a therapeutic drug for cancer including the above (Non-patent Document 1). Furthermore, it has been shown that PPARα antagonists inhibit the replication of HCV virus, and an effect as a therapeutic agent for HCV virus infection has been shown (Non-patent Document 2).
　ＰＰＡＲβ／δは、骨格筋を中心に生体内各組織に普遍的に発現しており、ＰＰＡＲβ／δの活性化により、骨格筋における脂肪酸の異化、ＨＤＬコレステロールの増加、インスリン抵抗性の改善、肥満の抑制などが誘導されることが明らかとなってきている（非特許文献３、非特許文献４）。最近では、ＰＰＡＲβ／δのアンタゴニストが、HCVウイルスのRNA複製を阻害することが確認され、C型肝炎治療薬として期待されている（非特許文献５）。さらに、ＰＰＡＲβ／δの選択的アンタゴニストが、マウスに発症した炎症性皮膚疾患の１つである乾癬の治療に有効であることが報告されている（非特許文献６）。その他にも、ＰＰＡＲβ／δアンタゴニストのSR13904が、肺癌、乳癌及び肝臓癌を含む、種々の癌細胞株に対し、その増殖と生存を阻害することが報告されている（非特許文献７）。 PPARβ / δ is ubiquitously expressed in various tissues in the body centering on skeletal muscle, and activation of PPARβ / δ causes fatty acid catabolism in skeletal muscle, increase in HDL cholesterol, improvement in insulin resistance, obesity It has been clarified that the suppression or the like is induced (Non-Patent Document 3, Non-Patent Document 4). Recently, an antagonist of PPARβ / δ has been confirmed to inhibit RNA replication of HCV virus, and is expected as a therapeutic agent for hepatitis C (Non-patent Document 5). Furthermore, it has been reported that a selective antagonist of PPARβ / δ is effective for the treatment of psoriasis, which is one of inflammatory skin diseases developed in mice (Non-patent Document 6). In addition, it has been reported that SR13904, a PPARβ / δ antagonist, inhibits the growth and survival of various cancer cell lines including lung cancer, breast cancer and liver cancer (Non-patent Document 7).
　ＰＰＡＲγは、脂肪細胞やマクロファージに高発現しており、脂肪細胞の分化、インスリン感受性の獲得などに関与するタンパク質を誘導する。アイソフォームとして、ＰＰＡＲγ１、γ２及びγ３の少なくとも３種類の存在が確認されており、これらは、選択的スプライシングの結果、発現すると考えられている。
　ＰＰＡＲγと疾患との関連性については、これまでに多くの報告が行われている。
　例えば、ＰＰＡＲγアンタゴニストが糖尿病薬あるいは抗肥満薬として有効であることが開示されている（非特許文献８～１１）。また、ＰＰＡＲγの機能を抑制すると、骨組織の発生が誘導されること（非特許文献１２及び１３）、ＰＰＡＲγアンタゴニストであるBADGEが骨芽細胞への分化を促進しマウスの骨量を増加させること（非特許文献１４）などが見出されており、ＰＰＡＲγアンタゴニストが骨組織の形成に機能し、例えば、骨粗鬆症などの治療薬として有効であることが示されている。さらに、ＰＰＡＲγは、大腸癌、乳癌、前立腺癌、膵臓癌、肺癌、骨髄性白血病細胞及びリンパ性白血病細胞などの多くの癌細胞においても、その発現が確認されている（非特許文献１５～１７）。Tsukaharaらは、ＰＰＡＲγアンタゴニストであるサイクリックフォスファジン酸（Cyclic phosphatidic acid）が結腸癌細胞の増殖を抑制することを報告しており（非特許文献１８）、また、Zaytsevaらは、ＰＰＡＲγアンタゴニストが乳癌細胞の増殖を抑制することを報告している（非特許文献１９）。Schaeferらは、ＰＰＡＲγアンタゴニストであるT0070907が、肝癌細胞のアノイキスを誘導し抗腫瘍活性を示すことを報告している（非特許文献２０）。以上のように、ＰＰＡＲγアンタゴニストは、抗癌剤としても、種々の癌に対し有効であることが示されている。 PPARγ is highly expressed in adipocytes and macrophages and induces proteins involved in adipocyte differentiation and acquisition of insulin sensitivity. As isoforms, at least three types of PPARγ1, γ2 and γ3 have been confirmed, and these are considered to be expressed as a result of alternative splicing.
There have been many reports on the relationship between PPARγ and diseases.
For example, it is disclosed that a PPARγ antagonist is effective as a diabetic drug or an anti-obesity drug (Non-Patent Documents 8 to 11). Moreover, suppression of the function of PPARγ induces the development of bone tissue (Non-patent Documents 12 and 13), and the PPARγ antagonist BADGE promotes differentiation into osteoblasts and increases bone mass in mice. (Non-Patent Document 14) and the like have been found, and PPARγ antagonists function in the formation of bone tissue and have been shown to be effective as therapeutic agents for osteoporosis, for example. Furthermore, the expression of PPARγ has been confirmed in many cancer cells such as colorectal cancer, breast cancer, prostate cancer, pancreatic cancer, lung cancer, myeloid leukemia cells and lymphoid leukemia cells (Non-Patent Documents 15 to 17). ). Tsukahara et al. Have reported that cyclic phosphatidic acid, a PPARγ antagonist, suppresses the growth of colon cancer cells (Non-patent Document 18), and Zaytseva et al. It has been reported that cell proliferation is suppressed (Non-patent Document 19). Schaefer et al. Have reported that T0070907, a PPARγ antagonist, induces anoikis in liver cancer cells and exhibits antitumor activity (Non-patent Document 20). As described above, PPARγ antagonists have been shown to be effective against various cancers as anticancer agents.
　すでに、ＰＰＡＲαに対する外因性リガンドとしてフェノフィブラート，ベザフィブラート，クロフィブラートなどのいわゆるフィブラート系の薬剤が、また、ＰＰＡＲγに対する外因性リガンドとしてはトログリタゾンやピオグリタゾンのようないわゆるチアゾリジン系の薬剤が知られている。また、フィブラート系、チアゾリジン系以外で、ＰＰＡＲの各アイソフォームをターゲットとする化合物として、置換フェニルプロピオン酸誘導体がいくつか報告されている（特許文献１～６を参照のこと）。 So-called fibrates such as fenofibrate, bezafibrate and clofibrate are already known as exogenous ligands for PPARα, and so-called thiazolidine-based agents such as troglitazone and pioglitazone are known as exogenous ligands for PPARγ. Some substituted phenylpropionic acid derivatives have been reported as compounds that target each PPAR isoform other than fibrates and thiazolidines (see Patent Documents 1 to 6).
ＷＯ０１／０９２２０１号WO01 / 092201 ＷＯ００／７５１０３号WO00 / 75103 ＷＯ２００４／０５６７４８号WO2004 / 0567748 ＷＯ２００４／０４６０９１号WO2004 / 046091 ＷＯ０３／０５１８２１号WO03 / 051821 ＷＯ０２／０９８８４０号WO02 / 098840
　本発明は、新規アセチレンアミド誘導体であって、ＰＰＡＲα、ＰＰＡＲβ／δ、ＰＰＡＲγのすべてに対するアンタゴニスト活性を有する化合物、ＰＰＡＲγに対するアンタゴニスト活性を有する化合物の提供を目的とする。 An object of the present invention is to provide a novel acetylenamide derivative, a compound having antagonist activity against all of PPARα, PPARβ / δ and PPARγ, and a compound having antagonist activity against PPARγ.
　また、本発明は、当該新規アセチレンアミド誘導体を有効成分として含むＰＰＡＲα、ＰＰＡＲβ／δ、ＰＰＡＲγのすべてに対する転写活性抑制剤、ＰＰＡＲγに対する転写活性抑制剤の提供を目的とする。 Another object of the present invention is to provide a transcriptional activity inhibitor for all of PPARα, PPARβ / δ, and PPARγ, and a transcriptional activity inhibitor for PPARγ, which contain the novel acetylenamide derivative as an active ingredient.
　さらに、本発明は、当該新規アセチレンアミド誘導体を有効成分として含む、ＰＰＡＲα、ＰＰＡＲβ／δ、及び／又はＰＰＡＲγの転写活性の異常（亢進）に起因する疾患（例えば、種々の組織に発症した癌、炎症性皮膚疾患、糖尿病、肥満症など）、又は、ＰＰＡＲα、ＰＰＡＲβ／δ、及び／又はＰＰＡＲγが関与していると考えられているHCVウイルスの感染により発症する疾患の治療剤及び／又は予防剤の提供を目的とする。 Furthermore, the present invention relates to a disease caused by abnormal (enhanced) transcriptional activity of PPARα, PPARβ / δ, and / or PPARγ containing the novel acetylenamide derivative as an active ingredient (for example, cancer that has developed in various tissues, Inflammatory skin diseases, diabetes, obesity, etc.) or therapeutic and / or prophylactic agent for diseases caused by infection with HCV virus that is thought to involve PPARα, PPARβ / δ, and / or PPARγ The purpose is to provide.
　本発明は、ＰＰＡＲα、ＰＰＡＲβ／δ、及び／又はＰＰＡＲγの転写活性の異常（亢進）に起因する疾患（例えば、種々の組織に発症した癌、炎症性皮膚疾患、糖尿病、肥満症など）、又は、ＰＰＡＲα、ＰＰＡＲβ／δ、及び／又はＰＰＡＲγが関与していると考えられているHCVウイルスの感染により発症する疾患の治療方法又は予防方法を提供する。 The present invention relates to diseases caused by abnormal (enhanced) transcriptional activity of PPARα, PPARβ / δ, and / or PPARγ (eg, cancer that has developed in various tissues, inflammatory skin diseases, diabetes, obesity, etc.), or , PPARα, PPARβ / δ, and / or PPARγ, a method for treating or preventing a disease caused by infection with HCV virus, which is considered to be involved.
　本発明者らは、上記事情に鑑み、鋭意研究を行ったところ、新規アセチレンアミド誘導体を合成し、当該新規アセチレンアミド誘導体であって、ＰＰＡＲα、ＰＰＡＲβ／δ、ＰＰＡＲγのすべてに対するアンタゴニスト活性有する化合物、ＰＰＡＲに対するアンタゴニスト活性を有する化合物を見出し、本発明を完成させた。 In view of the above circumstances, the present inventors have conducted extensive research and synthesized a novel acetylenamide derivative, which is a compound having an antagonist activity against all of PPARα, PPARβ / δ, and PPARγ, A compound having antagonist activity against PPAR has been found and the present invention has been completed.
　すなわち本発明は、 一般式( I )：
Figure JPOXMLDOC01-appb-C000007
 ［式中、Ｒ１は無置換又は置換基を有しても良いフェニル基、ピリミジン－２－イル基、２－ピリジル基、２－チエニル基、ピペリジノ基、シクロヘキシル基、アダマンチル基、トリフルオロメチル基、メトキシ基、フェノキシ基、４－フルオロフェノキシ基、アニリノ基を表し、Ｒ２は水素原子又はフッ素原子を表し、Ｒ３は炭素数１から６の直鎖状又は分岐状アルキル基を表し、Ｒ４は無置換又は置換基を有しても良いフェニル基、炭素数５～７のシクロアルキル基、ピリジル基、チエニル基を表す］で表されるアセチレンアミド誘導体若しくはその薬学上許容される塩又はそれらの水和物、及び該アセチレンアミド誘導体の製造方法である。 That is, the present invention relates to the general formula (I):
Figure JPOXMLDOC01-appb-C000007
 [Wherein R 1 is unsubstituted or optionally substituted phenyl, pyrimidin-2-yl, 2-pyridyl, 2-thienyl, piperidino, cyclohexyl, adamantyl, trifluoromethyl A methoxy group, a phenoxy group, a 4-fluorophenoxy group, an anilino group, R 2 represents a hydrogen atom or a fluorine atom, R 3 represents a linear or branched alkyl group having 1 to 6 carbon atoms, R 4 represents an unsubstituted or optionally substituted phenyl group, a cycloalkyl group having 5 to 7 carbon atoms, a pyridyl group, a thienyl group], or a pharmaceutically acceptable salt thereof. Or a hydrate thereof, and a process for producing the acetylenamide derivative.
　さらに、本発明は上記一般式( I )で表される新規アセチレンアミド誘導体であって、ＰＰＡＲα、ＰＰＡＲβ／δ、ＰＰＡＲγのすべての転写活性を抑制するアンタゴニスト、ＰＰＡＲγの転写活性を抑制するＰＰＡＲγに対するアンタゴニストである。 Furthermore, the present invention is a novel acetylenamide derivative represented by the above general formula (I), an antagonist that suppresses all transcription activities of PPARα, PPARβ / δ, and PPARγ, and an antagonist to PPARγ that suppresses the transcription activity of PPARγ. It is.
　また、本発明は上記一般式( I )で表される新規アセチレンアミド誘導体であって、ＰＰＡＲα、ＰＰＡＲβ／δ、ＰＰＡＲγのすべてに対する転写活性抑制剤、ＰＰＡＲγに対する転写活性抑制剤である。 Further, the present invention is a novel acetylenamide derivative represented by the above general formula (I), which is a transcription activity inhibitor for all of PPARα, PPARβ / δ, and PPARγ, and a transcription activity inhibitor for PPARγ.
　さらに、本発明は、上記一般式( I )で表される新規アセチレンアミド誘導体若しくはその薬学上許容される塩又は水和物を含有する医薬、又は医薬組成物である。 Furthermore, the present invention is a pharmaceutical or a pharmaceutical composition containing the novel acetylenamide derivative represented by the above general formula (I) or a pharmaceutically acceptable salt or hydrate thereof.
　さらにまた、本発明は、上記一般式( I )で表される化合物の製造に適する、以下の一般式( II )の化合物である。
Figure JPOXMLDOC01-appb-C000008
 ［式中、Ｒ１は無置換又は置換基を有しても良いフェニル基、ピリミジン－２－イル基、２－ピリジル基、２－チエニル基、ピペリジノ基、シクロヘキシル基、アダマンチル基、トリフルオロメチル基、メトキシ基、フェノキシ基、４－フルオロフェノキシ基、アニリノ基を表し、Ｒ２は水素原子又はフッ素原子を表し、Ｒ３は炭素数１から６の直鎖状又は分岐状アルキル基を表す］ Furthermore, this invention is a compound of the following general formula (II) suitable for manufacture of the compound represented by the said general formula (I).
Figure JPOXMLDOC01-appb-C000008
 [Wherein R 1 is unsubstituted or optionally substituted phenyl, pyrimidin-2-yl, 2-pyridyl, 2-thienyl, piperidino, cyclohexyl, adamantyl, trifluoromethyl A methoxy group, a phenoxy group, a 4-fluorophenoxy group, an anilino group, R 2 represents a hydrogen atom or a fluorine atom, and R 3 represents a linear or branched alkyl group having 1 to 6 carbon atoms]
　さらに、本発明は、上記式( II )で表される化合物を中間体として、上記式( I )で表される化合物を製造する方法である。 Furthermore, the present invention is a method for producing a compound represented by the above formula (I) using the compound represented by the above formula (II) as an intermediate.
　本発明により、新規アセチレンアミド誘導体及び当該新規アセチレンアミド誘導体であって、ＰＰＡＲα、ＰＰＡＲβ／δ、ＰＰＡＲγのすべてに対するアンタゴニスト、ＰＰＡＲγに対するアンタゴニストが提供される。 According to the present invention, there are provided a novel acetylenamide derivative and the novel acetylenamide derivative, which are antagonists for all of PPARα, PPARβ / δ, and PPARγ, and antagonists for PPARγ.
　また、本発明により、ＰＰＡＲα、ＰＰＡＲβ／δ、ＰＰＡＲγのすべてに対する転写活性抑制剤、ＰＰＡＲγに対する転写活性抑制剤が提供される。 The present invention also provides a transcriptional activity inhibitor for all of PPARα, PPARβ / δ, and PPARγ, and a transcriptional activity inhibitor for PPARγ.
　さらに、本発明により、ＰＰＡＲα、ＰＰＡＲβ／δ、又は、ＰＰＡＲγの転写活性の異常によって惹起される疾患、例えば、癌（腎臓癌、肺癌、乳癌、肝臓癌、大腸癌、結腸癌、前立腺癌、膵臓癌、骨髄性白血病及びリンパ性白血病など）、炎症性皮膚疾患（例えば、乾癬など）、肥満症や糖尿病などのメタボリック症候群、骨の形成不良あるいは骨形成速度よりも骨吸収速度が高くなるなど骨組織形成及び吸収のバランスが崩れることにより発症する疾患（例えば、骨粗鬆症など）などの予防又は治療のための医薬、ＰＰＡＲα、ＰＰＡＲβ／δ、又は、ＰＰＡＲγが関与していると考えられるHCVウイルスの感染症の予防又は治療のための医薬が提供される。 Furthermore, according to the present invention, diseases caused by abnormal transcription activity of PPARα, PPARβ / δ, or PPARγ, such as cancer (kidney cancer, lung cancer, breast cancer, liver cancer, colon cancer, colon cancer, prostate cancer, pancreas, etc. Cancer, myeloid leukemia and lymphocytic leukemia), inflammatory skin diseases (eg psoriasis), metabolic syndrome such as obesity and diabetes, bone formation failure or bone resorption rate higher than bone formation rate Infection with HCV virus, which is considered to involve PPARα, PPARβ / δ, or PPARγ, a medicine for prevention or treatment of diseases (for example, osteoporosis, etc.) that develop due to the imbalance between tissue formation and absorption A medicament for the prevention or treatment of the disease is provided.
　また、本発明の一般式( I )で示される化合物は、一般式( II )の中間体化合物を使用することで、迅速かつ効率的な製造が可能となる。 In addition, the compound represented by the general formula (I) of the present invention can be rapidly and efficiently produced by using the intermediate compound of the general formula (II).
本発明のＰＰＡＲγアンタゴニストと既存のＰＰＡＲγアンタゴニストとの作用機序の比較を示す。DMSO、ピオグリタゾン、GW9662、本発明の化合物１、化合物１２及び化合物１３を、アッセイ系に添加し、ルシフェラーゼ活性を測定した。縦軸は、DMSOを添加した場合の発光強度を１とした場合の発光強度の相対値である。The comparison of the action mechanism of the PPARγ antagonist of the present invention and the existing PPARγ antagonist is shown. DMSO, pioglitazone, GW9662, Compound 1, Compound 12 and Compound 13 of the present invention were added to the assay system, and luciferase activity was measured. The vertical axis represents the relative value of the emission intensity when the emission intensity when DMSO is added is 1. 本発明のＰＰＡＲγアンタゴニストと既存のＰＰＡＲγアンタゴニストとの作用機序の比較を示す。DMSO、ピオグリタゾン、GW9662、本発明の化合物１、化合物１２及び化合物１３を、アッセイ系に添加し、ルシフェラーゼ活性を測定した。縦軸は、DMSOを添加した場合の発光強度を１とした場合の発光強度の相対値である。The comparison of the action mechanism of the PPARγ antagonist of the present invention and the existing PPARγ antagonist is shown. DMSO, pioglitazone, GW9662, Compound 1, Compound 12 and Compound 13 of the present invention were added to the assay system, and luciferase activity was measured. The vertical axis represents the relative value of the emission intensity when the emission intensity when DMSO is added is 1. 本発明の化合物の脂肪細胞分化への効果を検討した結果を示す。　Ａは、10nM、100nM、1μM及び10μMの化合物１２を加えた場合における、脂肪細胞への分化の様子を観察した結果である。赤色（図では暗色）に染色されている部分が、分化した脂肪細胞である。Ｂは、ＰＰＡＲγアゴニストであるピオグリタゾンの存在下において、化合物１２を添加した場合の脂肪細胞への分化を観察した結果である。Ｂの上側はピオグリタゾンのみを添加した結果であり、下側はピオグリタゾンと化合物１２を添加した結果である。pio：ピオグリタゾン、化１２：化合物１２The result of having investigated the effect on the adipocyte differentiation of the compound of this invention is shown. A is the result of observing the state of differentiation into adipocytes when 10 nM, 100 nM, 1 μM and 10 μM compound 12 was added. The portion stained in red (dark color in the figure) is differentiated adipocytes. B is the result of observing differentiation into adipocytes when Compound 12 is added in the presence of pioglitazone, which is a PPARγ agonist. The upper side of B is the result of adding only pioglitazone, and the lower side is the result of adding pioglitazone and Compound 12. pio: Pioglitazone, Chemical formula 12: Compound 12 本発明の化合物の脂肪細胞分化への影響を検討した結果を示す。　ＰＰＡＲγアゴニストであるピオグリタゾンの存在下において、化合物１３を添加した場合の脂肪細胞への分化を観察した結果である。490mnの吸光度を縦軸に示す。ピオグリタゾン1μMの存在下において、化合物１３を１μM、10μＭ添加して、その影響を確認した。The result of having investigated the influence on the adipocyte differentiation of the compound of this invention is shown. It is the result of observing differentiation into adipocytes when compound 13 is added in the presence of pioglitazone which is a PPARγ agonist. The absorbance at 490 mn is shown on the vertical axis. In the presence of 1 μM pioglitazone, 1 μM and 10 μM of Compound 13 were added to confirm the effect. 本発明のＰＰＡＲγアンタゴニストと既存のＰＰＡＲγアンタゴニストの脂肪細胞分化への抑制効果を比較した結果を示す。　ＰＰＡＲγアゴニストであるピオグリタゾンの存在下において、化合物１３又はGW9662を添加した場合の脂肪細胞への分化を観察した。ＰＰＡＲγアンタゴニストを添加しない場合の490mnの吸光度を100%として、脂肪細胞への分化の抑制効果を相対値で示した。The result of having compared the inhibitory effect on the adipocyte differentiation of the PPARγ antagonist of the present invention and the existing PPARγ antagonist is shown. In the presence of PPARγ agonist pioglitazone, differentiation into adipocytes was observed when compound 13 or GW9662 was added. The absorbance at 490 mn when no PPARγ antagonist was added was taken as 100%, and the effect of inhibiting differentiation into adipocytes was shown as a relative value.
　本発明の実施形態の１つは、一般式( I )で表される新規アセチレンアミド誘導体若しくはその薬学上許容される塩又は水和物、あるいは、当該新規アセチレンアミド誘導体であって、ＰＰＡＲα、ＰＰＡＲβ／δ、ＰＰＡＲγのすべてに対するアンタゴニスト、ＰＰＡＲγに対するアンタゴニストである。ここで、「アンタゴニスト」とは、ＰＰＡＲα、ＰＰＡＲβ／δ、及び／又はＰＰＡＲγと何らかの相互作用をして、ＰＰＡＲα、ＰＰＡＲβ／δ、又はＰＰＡＲγによる標的遺伝子の転写活性化を抑制する化合物のことである。 One of the embodiments of the present invention is a novel acetylenamide derivative represented by the general formula (I) or a pharmaceutically acceptable salt or hydrate thereof, or the novel acetylenamide derivative, wherein PPARα, PPARβ / Δ, antagonist to all of PPARγ, antagonist to PPARγ. Here, the “antagonist” is a compound that interacts with PPARα, PPARβ / δ, and / or PPARγ to suppress transcriptional activation of a target gene by PPARα, PPARβ / δ, or PPARγ. .
　一般式( I )において、Ｒ１は、無置換又は置換基を有しても良いフェニル基、ピリミジン－２－イル基、２－ピリジル基、２－チエニル基、ピペリジノ基、シクロヘキシル基、アダマンチル基、トリフルオロメチル基、メトキシ基、フェノキシ基、４－フルオロフェノキシ基、アニリノ基を表し、好ましくは、好ましくはピリミジン－２－イル基、アダマンチル基、４－フルオロフェノキシ基である。
　Ｒ２は水素原子またはフッ素原子を表し、好ましくは水素原子である。
　Ｒ３は炭素数１から６の直鎖状又は分岐状アルキル基を表し、好ましくは、炭素数１から５の直鎖状アルキル基である。
　Ｒ４は無置換又は置換基を有しても良いフェニル基（例えば、フェニル基、２－メチルフェニル基、３－メチルフェニル基、２－メトキシフェニル基、４－メトキシフェニル基、２－フルオロフェニル基、３－フルオロフェニル基、４－フルオロフェニル基、２－クロロフェニル基、３－クロロフェニル基、２－ブロモフェニル基、２－トリフルオロメチル基など）、炭素数５～７のシクロアルキル基、ピリジル基、チエニル基を表し、好ましくは無置換フェニル基、２－メチルフェニル基、３－メチルフェニル基、２－メトキシフェニル基、４－メトキシフェニル基、２－フルオロフェニル基、３－フルオロフェニル基、４－フルオロフェニル基、２－クロロフェニル基、３－クロロフェニル基、２－ブロモフェニル基、２－トリフルオロメチル基、ピリジン－２－イル基、２－チエニル基である。 In the general formula (I), R 1 is an unsubstituted or optionally substituted phenyl group, pyrimidin-2-yl group, 2-pyridyl group, 2-thienyl group, piperidino group, cyclohexyl group, adamantyl group , A trifluoromethyl group, a methoxy group, a phenoxy group, a 4-fluorophenoxy group, and an anilino group, preferably a pyrimidin-2-yl group, an adamantyl group, and a 4-fluorophenoxy group.
R 2 represents a hydrogen atom or a fluorine atom, preferably a hydrogen atom.
R 3 represents a linear or branched alkyl group having 1 to 6 carbon atoms, preferably a linear alkyl group having 1 to 5 carbon atoms.
R 4 is an unsubstituted or optionally substituted phenyl group (for example, phenyl group, 2-methylphenyl group, 3-methylphenyl group, 2-methoxyphenyl group, 4-methoxyphenyl group, 2-fluorophenyl). Group, 3-fluorophenyl group, 4-fluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 2-bromophenyl group, 2-trifluoromethyl group), cycloalkyl group having 5 to 7 carbon atoms, pyridyl Group, a thienyl group, preferably an unsubstituted phenyl group, 2-methylphenyl group, 3-methylphenyl group, 2-methoxyphenyl group, 4-methoxyphenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 2-bromophenyl group, 2-trifluoro A methyl group, a pyridin-2-yl group, and a 2-thienyl group;
　一般式( I )で表される本発明の化合物は、一般式( I )で表される新規アセチレンアミド誘導体のみならず、その塩又はそれらの溶媒和物若しくは水和物であってもよい。新規アセチレンアミド誘導体の塩は特に限定されるものではなく、慣用の塩、例えば、ナトリウム塩、カリウム塩、リチウム塩等のアルカリ金属塩；カルシウム塩、マグネシウム塩等のアルカリ土類金属塩；アルミニウム塩等の金属塩が挙げられ、好ましくは薬学上許容されるものである。 The compound of the present invention represented by the general formula (I) may be not only a novel acetylenamide derivative represented by the general formula (I) but also a salt thereof or a solvate or hydrate thereof. The salt of the novel acetylenamide derivative is not particularly limited, and is a conventional salt, for example, an alkali metal salt such as sodium salt, potassium salt or lithium salt; an alkaline earth metal salt such as calcium salt or magnesium salt; aluminum salt And the like, and preferably pharmaceutically acceptable.
　また、一般式( I )で表される新規アセチレンアミド誘導体には、特に断らない限り、その互変異性体、鏡像異性体等の立体異性体も含まれる。すなわち、一般式( I )で表される新規アセチレンアミド誘導体中に、１個又は２個以上の不斉炭素が含まれる場合、不斉炭素の立体化学については、それぞれ独立して（Ｒ）体又は（Ｓ）体のいずれかをとることができ、該誘導体の鏡像異性体又はジアステレオ異性体などの立体異性体として存在することがある。
　後述の本発明の医薬の有効成分としては、純粋な形態の任意の立体異性体、立体異性体の任意の混合物、ラセミ体などを用いることが可能である。 Further, the novel acetylenamide derivatives represented by the general formula (I) include stereoisomers such as tautomers and enantiomers thereof unless otherwise specified. That is, when one or more asymmetric carbons are contained in the novel acetylenamide derivative represented by the general formula (I), the stereochemistry of the asymmetric carbons is independently (R) isomer. Alternatively, it can take either (S) form and may exist as a stereoisomer such as an enantiomer or diastereomer of the derivative.
As an active ingredient of the medicament of the present invention described later, it is possible to use any stereoisomer in a pure form, any mixture of stereoisomers, racemate and the like.
　また、本発明の他の実施形態は、一般式( I I )示される化合物である。一般式( II )で示される化合物は、一般式( I )の新規アセチレンアミド誘導体を製造するのに適した中間体の化合物である。
　一般式( I )の化合物を製造する場合、限定はしないが、例えば、一般式( I )の化合物は一般式( II )で示される化合物と、後述の式(VIII )で表される化合物との縮合反応等により合成することができる。このような合成過程を経ることで、迅速、簡便に一般式( I )の化合物を合成することができる。
　一般式( II )において、Ｒ１は、無置換又は置換基を有しても良いフェニル基、ピリミジン－２－イル基、２－ピリジル基、２－チエニル基、ピペリジノ基、シクロヘキシル基、アダマンチル基、トリフルオロメチル基、メトキシ基、フェノキシ基、４－フルオロフェノキシ基、アニリノ基を表し、好ましくは、好ましくはピリミジン－２－イル基、アダマンチル基、４－フルオロフェノキシ基である。
　Ｒ２は水素原子またはフッ素原子を表し、好ましくは水素原子である。
　Ｒ３は炭素数１から６の直鎖状又は分岐状アルキル基を表し、好ましくは、炭素数１から５の直鎖状アルキル基である。 Another embodiment of the present invention is a compound represented by the general formula (I I). The compound represented by the general formula (II) is an intermediate compound suitable for producing a novel acetylenamide derivative of the general formula (I).
When producing the compound of the general formula (I), but not limited, for example, the compound of the general formula (I) is a compound represented by the general formula (II) and a compound represented by the following formula (VIII) It can be synthesized by a condensation reaction of Through such a synthesis process, the compound of the general formula (I) can be synthesized quickly and easily.
In the general formula (II), R 1 is an unsubstituted or optionally substituted phenyl group, pyrimidin-2-yl group, 2-pyridyl group, 2-thienyl group, piperidino group, cyclohexyl group, adamantyl group , A trifluoromethyl group, a methoxy group, a phenoxy group, a 4-fluorophenoxy group, and an anilino group, preferably a pyrimidin-2-yl group, an adamantyl group, and a 4-fluorophenoxy group.
R 2 represents a hydrogen atom or a fluorine atom, preferably a hydrogen atom.
R 3 represents a linear or branched alkyl group having 1 to 6 carbon atoms, preferably a linear alkyl group having 1 to 5 carbon atoms.
　一般式( I )で示されるＰＰＡＲγに選択的なアンタゴニスト及びその塩としては、限定はしないが、例えば、次のものが挙げられる。
N-(5-(3-phenylpropiolamido)-2-propoxybenzyl)-4-(pyrimidin-2-yl)benzamide
［Ｎ―（５－（３－フェニルプロピオルアミド）－２－プロポキシベンジル）－４－（ピリミジン－２－イル）ベンズアミド］、
N-(2-propoxy-5-(3-o-tolylpropiolamido)benzyl)-4-(pyrimidin-2-yl)benzamide
［Ｎ－（２－プロポキシ－５－（３－ｏ－トルイルプロピオルアミド）ベンジル）－４－（ピリミジン－２－イル）ベンズアミド］、
N-(5-(3-(2-chlorophenyl)propiolamido)-2-propoxybenzyl)-4-(pyrimidin-2-yl)benzamide
［Ｎ－（５－（３－（２－クロロフェニル）プロピオルアミド）－２－プロポキシベンジル）－４－（ピリミジン－２－イル）ベンズアミド］、
N-(2-propoxy-5-(3-(pyridin-2-yl)propiolamido)benzyl)-4-(pyrimidin-2-yl)benzamide hydrochloride
［Ｎ－（２－プロポキシ－５－（３－ピリジン－２－イル）プロピオルアミド）ベンジル）－４－（ピリミジン－２－イル）ベンズアミド　ハイドロクロライド］
4-(4-Fluorophenoxy)-N-(2-propoxy-5-(3-(thiophen-2-yl) propionamido)benzyl)benzamide
［４－（４－フルオロフェノキシ）－Ｎ－（２－プロポキシ－５－（３－（チオフェン－２－イル）プロピオアミド）ベンジル）ベンズアミド］ The antagonists and salts thereof selective for PPARγ represented by the general formula (I) include, but are not limited to, the following.
N- (5- (3-phenylpropiolamido) -2-propoxybenzyl) -4- (pyrimidin-2-yl) benzamide
[N- (5- (3-phenylpropiolamido) -2-propoxybenzyl) -4- (pyrimidin-2-yl) benzamide],
N- (2-propoxy-5- (3-o-tolylpropiolamido) benzyl) -4- (pyrimidin-2-yl) benzamide
[N- (2-propoxy-5- (3-o-toluylpropiolamido) benzyl) -4- (pyrimidin-2-yl) benzamide],
N- (5- (3- (2-chlorophenyl) propiolamido) -2-propoxybenzyl) -4- (pyrimidin-2-yl) benzamide
[N- (5- (3- (2-chlorophenyl) propiolamido) -2-propoxybenzyl) -4- (pyrimidin-2-yl) benzamide],
N- (2-propoxy-5- (3- (pyridin-2-yl) propiolamido) benzyl) -4- (pyrimidin-2-yl) benzamide hydrochloride
[N- (2-propoxy-5- (3-pyridin-2-yl) propiolamido) benzyl) -4- (pyrimidin-2-yl) benzamide hydrochloride]
4- (4-Fluorophenoxy) -N- (2-propoxy-5- (3- (thiophen-2-yl) propionamido) benzyl) benzamide
[4- (4-Fluorophenoxy) -N- (2-propoxy-5- (3- (thiophen-2-yl) propioamido) benzyl) benzamide]
　本発明の一般式( I )で表される化合物のうち、式中、Ｒ１はピリミジン－２－イル基、Ｒ２は水素原子、Ｒ３は炭素数３の直鎖状アルキル基、Ｒ４は無置換または置換基を有しても良いフェニル基、炭素数５～７のシクロアルキル基、ピリジル基で表される化合物( Ia )は、以下の方法により製造することができる(スキーム１)。
Figure JPOXMLDOC01-appb-C000009
 スキーム１ Among the compounds represented by the general formula (I) of the present invention, in the formula, R 1 is a pyrimidin-2-yl group, R 2 is a hydrogen atom, R 3 is a linear alkyl group having 3 carbon atoms, R 4 Is an unsubstituted or optionally substituted phenyl group, a cycloalkyl group having 5 to 7 carbon atoms, and a compound (Ia) represented by a pyridyl group can be produced by the following method (Scheme 1) .
Figure JPOXMLDOC01-appb-C000009
 Scheme 1
　　　すなわち、一般式( Ia )：
Figure JPOXMLDOC01-appb-C000010
 　［式中、Ｒ３は炭素数１から６の直鎖状または分岐状アルキル基を表し、Ｒ４は無置換または置換基を有しても良いフェニル基、炭素数５～７のシクロアルキル基、ピリジル基を表す］で表される化合物は、以下の：
Figure JPOXMLDOC01-appb-C000011
 で表される化合物(III)と、以下の：
Figure JPOXMLDOC01-appb-C000012
 ［式中、Ｒ３は前記と同義であり、Ｘは臭素またはヨウ素である］で表される化合物(VII)とを反応させ（ａ工程）、得られた以下の：
Figure JPOXMLDOC01-appb-C000013
 ［式中、Ｒ３は前記と同義である］で表される化合物( IV )とt-ブチルカルバメートを還元的アミドアルキル化反応させた後酸処理（ｂ工程）することにより製造することができる以下の：
Figure JPOXMLDOC01-appb-C000014
 ［式中、Ｒ３は前記と同義である］で表される化合物( V )と４－（ピリミジン－２－イル）安息香酸を縮合させる（ｃ工程）ことにより製造することができる以下の：
Figure JPOXMLDOC01-appb-C000015
 ［式中、Ｒ３は前記と同義である］で表される化合物( VI )を還元する（ｄ工程）ことにより製造することができる以下の：
Figure JPOXMLDOC01-appb-C000016
 ［式中、Ｒ３は前記と同義である］で表される重要中間体( IIa)と以下の：
Figure JPOXMLDOC01-appb-C000017
 ［式中、Ｒ４は前記と同義である］で表わされる化合物( VIII )で表される化合物と縮合する（ｅ工程）ことにより合成することができる。 That is, the general formula (Ia):
Figure JPOXMLDOC01-appb-C000010
 [Wherein R 3 represents a linear or branched alkyl group having 1 to 6 carbon atoms, R 4 represents a phenyl group which may be unsubstituted or substituted, or a cycloalkyl group having 5 to 7 carbon atoms. Represents a pyridyl group], the compound represented by the following:
Figure JPOXMLDOC01-appb-C000011
 Compound (III) represented by the following:
Figure JPOXMLDOC01-appb-C000012
 [Wherein R 3 has the same meaning as described above, and X is bromine or iodine] (reaction a), and the following:
Figure JPOXMLDOC01-appb-C000013
 [Wherein R 3 is as defined above] and t-butyl carbamate and a reductive amide alkylation reaction followed by acid treatment (step b). below:
Figure JPOXMLDOC01-appb-C000014
 [Wherein R 3 is as defined above] and can be produced by condensing the compound (V) and 4- (pyrimidin-2-yl) benzoic acid (step c) as follows:
Figure JPOXMLDOC01-appb-C000015
 [Wherein R 3 has the same meaning as described above] and can be produced by reducing (step d) the following compound (VI):
Figure JPOXMLDOC01-appb-C000016
 [Wherein R 3 has the same meaning as defined above] and the following intermediate (IIa):
Figure JPOXMLDOC01-appb-C000017
 It can be synthesized by condensing with a compound represented by the compound (VIII) represented by [wherein R 4 has the same meaning as described above] (step e).
　ａ工程の反応は、テトラヒドロフランやジエチルエーテル、ＤＭＦやＤＭＳＯ等の溶媒中、塩基として、例えば水素化ナトリウムのようなアルカリ金属水素化物、ブチルリチウムのような有機金属化合物、リチウムジイソプロピルアミド、ナトリウムビス(トリメチルシリル)アミドのような金属アミドを用いる事ができる。反応温度としては－１００℃から１５０℃にて、好適には－８０℃から１００℃にて実施する事ができる。反応時間は通常１～４８時間、好ましくは２～２４時間である。 The reaction of step a is carried out in a solvent such as tetrahydrofuran, diethyl ether, DMF or DMSO as a base, for example, an alkali metal hydride such as sodium hydride, an organometallic compound such as butyl lithium, lithium diisopropylamide, sodium bis ( Metal amides such as trimethylsilyl) amide can be used. The reaction can be performed at -100 ° C to 150 ° C, preferably -80 ° C to 100 ° C. The reaction time is usually 1 to 48 hours, preferably 2 to 24 hours.
　ｂ工程の反応はトリエチルシランの存在下、トルエン、アセトニトリル、酢酸エチル、Ｎ，Ｎ－ジメチルホルムアミド等の溶媒中で実施する事ができる。反応温度としては０℃から１５０℃にて、好適には室温から１００℃にて実施する事ができる。反応時間は通常０．５～２４時間、好ましくは１～５時間である。 The reaction in step b can be carried out in a solvent such as toluene, acetonitrile, ethyl acetate, N, N-dimethylformamide in the presence of triethylsilane. The reaction temperature can be 0 to 150 ° C., preferably room temperature to 100 ° C. The reaction time is usually 0.5 to 24 hours, preferably 1 to 5 hours.
　c工程の反応は、テトラヒドロフランやジエチルエーテル、ジクロロメタンやクロロホルム、ヘキサン、ＤＭＦ等の溶媒中、縮合剤存在下、塩基としてトリエチルアミンやジイソプロピルエチルアミン、ピリジン、ルチジンの存在下、または非存在下実施する事ができる。反応温度としては－５０℃から１００℃にて、好適には－２０℃から５０℃にて実施する事ができる。反応時間は通常１～４８時間、好ましくは６～２４時間である。 The reaction in step c may be carried out in a solvent such as tetrahydrofuran, diethyl ether, dichloromethane, chloroform, hexane, or DMF in the presence of a condensing agent and in the presence or absence of triethylamine, diisopropylethylamine, pyridine, or lutidine as a base. it can. The reaction can be carried out at −50 to 100 ° C., preferably −20 to 50 ° C. The reaction time is usually 1 to 48 hours, preferably 6 to 24 hours.
　ｄ工程の反応はパラジウム担持活性炭、白金担持活性炭、酸化白金、ロジウム担持アルミナ等の金属触媒存在下、エタノール、メタノール、テトラヒドロフラン、酢酸エチル、Ｎ，Ｎ－ジメチルホルムアミド等の溶媒中、水素圧９８．１ｋＰａから４９１ｋＰａで実施する事ができる。反応温度としては０℃から１５０℃にて、好適には室温から１００℃にて実施する事ができる。反応時間は通常０．５～２４時間、好ましくは１～５時間である。 The reaction in step d is carried out in the presence of a metal catalyst such as palladium-supported activated carbon, platinum-supported activated carbon, platinum oxide, and rhodium-supported alumina in a solvent such as ethanol, methanol, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, and a hydrogen pressure of 98. It can be carried out at 1 kPa to 491 kPa. The reaction temperature can be 0 to 150 ° C., preferably room temperature to 100 ° C. The reaction time is usually 0.5 to 24 hours, preferably 1 to 5 hours.
　ｅ工程の反応は、テトラヒドロフランやジエチルエーテル、ジクロロメタンやクロロホルム、ヘキサン、ＤＭＦ等の溶媒中、縮合剤存在下、塩基としてトリエチルアミンやジイソプロピルエチルアミン、ピリジン、ルチジンの存在下、または非存在下実施する事ができる。反応温度としては－５０℃から１００℃にて、好適には－２０℃から５０℃にて実施する事ができる。反応時間は通常１～４８時間、好ましくは６～２４時間である。 The reaction in step e may be performed in a solvent such as tetrahydrofuran, diethyl ether, dichloromethane, chloroform, hexane, or DMF, in the presence of a condensing agent, and in the presence or absence of triethylamine, diisopropylethylamine, pyridine, or lutidine as a base. it can. The reaction can be carried out at −50 to 100 ° C., preferably −20 to 50 ° C. The reaction time is usually 1 to 48 hours, preferably 6 to 24 hours.
　本発明には、一般式( I )で示される新規アセチレンアミド誘導体を含むＰＰＡＲα、ＰＰＡＲβ／δ、ＰＰＡＲγのすべてに対する転写活性抑制剤（ＰＰＡＲα、ＰＰＡＲβ／δ、ＰＰＡＲγ標的遺伝子の転写を抑制する薬剤）、ＰＰＡＲγに対する転写活性抑制剤が含まれる。
　さらに、本発明の一般式( I )で示される新規アセチレンアミド誘導体であって、ＰＰＡＲα、ＰＰＡＲβ／δ、ＰＰＡＲγのすべてに対するアンタゴニスト、ＰＰＡＲγに対するアンタゴニストである化合物を含む医薬、又は医薬組成物も本発明の範囲に含まれる。
　本発明の医薬は、ＰＰＡＲα、ＰＰＡＲβ／δ、及び／又はＰＰＡＲγの機能異常、特に、その活性が亢進しすぎることによって発症する疾患等の治療剤又は予防剤として、また、ＰＰＡＲα、ＰＰＡＲβ／δ、及び／又はＰＰＡＲγが関与すると考えられているHCVウイルスの感染によって発症する疾患（HCVウイルス感染症という）の治療剤又は　予防剤として使用することができる。 In the present invention, a transcriptional activity inhibitor for all of PPARα, PPARβ / δ, and PPARγ containing a novel acetylenamide derivative represented by the general formula (I) (a drug that suppresses transcription of PPARα, PPARβ / δ, PPARγ target genes) And a transcriptional activity inhibitor for PPARγ.
Furthermore, the present invention also relates to a medicament or pharmaceutical composition comprising a novel acetylenamide derivative represented by the general formula (I) of the present invention, which is an antagonist to all of PPARα, PPARβ / δ and PPARγ, and a compound which is an antagonist to PPARγ. Included in the range.
The medicament of the present invention can be used as a therapeutic or prophylactic agent for PPARα, PPARβ / δ, and / or PPARγ dysfunction, in particular, a disease or the like that develops due to excessive enhancement of its activity, and PPARα, PPARβ / δ, And / or can be used as a therapeutic or prophylactic agent for a disease (referred to as HCV virus infection) caused by infection with HCV virus, which is thought to involve PPARγ.
　ＰＰＡＲαに関しては、ＰＰＡＲα特異的なアンタゴニストであるGW6471が腎細胞癌由来の細胞株のアポトーシスを誘導することを報告されており、ＰＰＡＲαアンタゴニストが腎臓癌などを含む癌の治療薬として利用可能である（非特許文献１）。また、ＰＰＡＲαアンタゴニストがHCVウイルスの複製を阻害することも報告されており、HCVウイルス感染症の治療薬として利用することができる（非特許文献２）。 Regarding PPARα, it has been reported that GW6471, a PPARα-specific antagonist, induces apoptosis of renal cell carcinoma-derived cell lines, and PPARα antagonists can be used as therapeutic agents for cancers including kidney cancer and the like ( Non-patent document 1). It has also been reported that PPARα antagonists inhibit HCV virus replication and can be used as therapeutic agents for HCV virus infection (Non-patent Document 2).
　ＰＰＡＲβ／δに関しては、ＰＰＡＲβ／δアンタゴニストが、HCVRNA複製抑制活性を示すことが報告されており、C型肝炎治療薬としての利用が可能である（非特許文献５）。さらに、ＰＰＡＲβ／δの選択的アンタゴニストは、炎症性皮膚疾患の１つである乾癬の治療に有効であることが報告されているため、炎症性皮膚疾患の治療薬としても利用可能である（非特許文献６）。その他にも、ＰＰＡＲβ／δアンタゴニストのSR13904が、肺癌、乳癌及び肝臓癌を含む、種々の癌細胞株に対し、その増殖と生存を阻害することが報告されており、抗癌剤としても利用できる（非特許文献７）。 Regarding PPARβ / δ, PPARβ / δ antagonists have been reported to exhibit HCV RNA replication inhibitory activity and can be used as therapeutic agents for hepatitis C (Non-patent Document 5). Furthermore, since selective antagonists of PPARβ / δ have been reported to be effective in the treatment of psoriasis, which is one of inflammatory skin diseases, they can also be used as therapeutic agents for inflammatory skin diseases (non- Patent Document 6). In addition, the PPARβ / δ antagonist SR13904 has been reported to inhibit the growth and survival of various cancer cell lines, including lung cancer, breast cancer and liver cancer, and can also be used as an anticancer agent (non-cancerous) Patent Document 7).
　ＰＰＡＲγに関しては、ＰＰＡＲγアンタゴニストが糖尿病薬あるいは抗肥満薬として有効であることが開示されている（非特許文献８～１１）。また、ＰＰＡＲγの機能を抑制すると、骨組織の発生が誘導されること（非特許文献１２及び１３）、ＰＰＡＲγアンタゴニストであるBADGEが骨芽細胞への分化を促進しマウスの骨量を増加させること（非特許文献１４）などが見出されており、ＰＰＡＲγアンタゴニストが骨組織の形成に機能し、例えば、骨粗鬆症などの治療薬として有効である。さらに、ＰＰＡＲγは、大腸癌、乳癌、前立腺癌、膵臓癌、肺癌、骨髄性白血病細胞及びリンパ性白血病細胞などの多くの癌細胞においても、その発現が確認されている（非特許文献１５～１７）。Tsukaharaらは、ＰＰＡＲγアンタゴニストであるサイクリックフォスファジン酸（Cyclic phosphatidic acid）が結腸癌細胞の増殖を抑制することを報告しており（非特許文献１８）、また、Zaytsevaらは、ＰＰＡＲγアンタゴニストが乳癌細胞の増殖を抑制することを報告している（非特許文献１９）。Schaeferらは、ＰＰＡＲγアンタゴニストであるT0070907が、肝癌細胞のアノイキスを誘導し抗腫瘍活性を示すことを報告している（非特許文献２０）。以上のように、ＰＰＡＲγアンタゴニストは、抗癌剤としても、種々の癌に対し有効である。 Regarding PPARγ, it is disclosed that PPARγ antagonists are effective as antidiabetic drugs or anti-obesity drugs (Non-Patent Documents 8 to 11). Moreover, suppression of the function of PPARγ induces the development of bone tissue (Non-patent Documents 12 and 13), and the PPARγ antagonist BADGE promotes differentiation into osteoblasts and increases bone mass in mice. (Non-Patent Document 14) and the like have been found, and PPARγ antagonists function in the formation of bone tissue and are effective as therapeutic agents for osteoporosis, for example. Furthermore, the expression of PPARγ has been confirmed in many cancer cells such as colorectal cancer, breast cancer, prostate cancer, pancreatic cancer, lung cancer, myeloid leukemia cells and lymphoid leukemia cells (Non-Patent Documents 15 to 17). ). Tsukahara et al. Have reported that cyclic phosphatidic acid, a PPARγ antagonist, suppresses the growth of colon cancer cells (Non-patent Document 18), and Zaytseva et al. It has been reported that cell proliferation is suppressed (Non-patent Document 19). Schaefer et al. Have reported that T0070907, a PPARγ antagonist, induces anoikis in liver cancer cells and exhibits antitumor activity (Non-patent Document 20). As described above, PPARγ antagonists are effective against various cancers as anticancer agents.
　従って、本発明の式(I)で表される新規アセチレンアミド誘導体は、種々の組織の癌、糖尿病、肥満症、高脂血症、高血圧症、動脈硬化症、高コレステロール症、HCVウイルス感染症、炎症性皮膚疾患（乾癬など）、骨組織の形成不良に起因する疾患などの治療薬又は予防薬の有効成分として使用することができる。 Therefore, the novel acetylenamide derivatives represented by the formula (I) of the present invention are cancers of various tissues, diabetes, obesity, hyperlipidemia, hypertension, arteriosclerosis, hypercholesterolemia, HCV virus infection It can be used as an active ingredient of a therapeutic or prophylactic agent for inflammatory skin diseases (such as psoriasis) and diseases caused by poor bone tissue formation.
　本発明の医薬の有効成分としては、上記一般式（Ｉ）で表される化合物のほか、生理学的に許容されるその塩を用いてもよい。塩としては、例えば、酸性基が存在する場合には、リチウム、ナトリウム、カリウム、マグネシウム、カルシウム等のアルカリ金属及びアルカリ土類金属塩；アンモニア、メチルアミン、ジメチルアミン、トリメチルアミン、ジシクロヘキシルアミン、トリス（ヒドロキシメチル）アミノメタン、Ｎ，Ｎ－ビス（ヒドロキシエチル）ピペラジン、２－アミノ－２－メチル－１－プロパノール、エタノールアミン、Ｎ－メチルグルカミン、Ｌ－グルカミン等のアミンの塩；又はリジン、δ－ヒドロキシリジン、アルギニンなどの塩基性アミノ酸との塩を形成することができる。塩基性基が存在する場合には、塩酸、臭化水素酸、硫酸、硝酸、リン酸等の鉱酸の塩；メタンスルホン酸、ベンゼンスルホン酸、パラトルエンスルホン酸、酢酸、プロピオン酸塩、酒石酸、フマル酸、マレイン酸、リンゴ酸、シュウ酸、コハク酸、クエン酸、安息香酸、マンデル酸、ケイ皮酸、乳酸、グリコール酸、グルクロン酸、アスコルビン酸、ニコチン酸、サリチル酸等の有機酸との塩；又はアスパラギン酸、グルタミン酸などの酸性アミノ酸との塩などを挙げることができる。
　さらに、本発明の医薬の有効成分として、一般式( I )で表される化合物又はその塩の溶媒和物若しくは水和物を用いることもできる。 As an active ingredient of the medicament of the present invention, a physiologically acceptable salt thereof may be used in addition to the compound represented by the above general formula (I). Examples of the salt include alkali metal and alkaline earth metal salts such as lithium, sodium, potassium, magnesium, and calcium; ammonia, methylamine, dimethylamine, trimethylamine, dicyclohexylamine, tris ( A salt of an amine such as hydroxymethyl) aminomethane, N, N-bis (hydroxyethyl) piperazine, 2-amino-2-methyl-1-propanol, ethanolamine, N-methylglucamine, L-glucamine; or lysine; Salts with basic amino acids such as δ-hydroxylysine and arginine can be formed. If basic groups are present, salts of mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; methanesulfonic acid, benzenesulfonic acid, paratoluenesulfonic acid, acetic acid, propionate, tartaric acid , Fumaric acid, maleic acid, malic acid, oxalic acid, succinic acid, citric acid, benzoic acid, mandelic acid, cinnamic acid, lactic acid, glycolic acid, glucuronic acid, ascorbic acid, nicotinic acid, salicylic acid and other organic acids Salts; or salts with acidic amino acids such as aspartic acid and glutamic acid.
Furthermore, a solvate or hydrate of the compound represented by the general formula (I) or a salt thereof can be used as the active ingredient of the medicament of the present invention.
　本発明の医薬は、有効成分である一般式( I )で表される化合物及び薬理学的に許容されるその塩、又はそれらの溶媒和物若しくはそれらの水和物自体を投与してもよいが、一般的には、有効成分である上記物質と１又は２以上の製剤用添加物とを含む医薬組成物の形態で投与することが望ましい。本発明の医薬の有効成分としては、上記の物質の２種以上を組み合わせて用いることができ、上記医薬組成物には、癌、糖尿病、高脂血症、高コレステロール症、高血圧症、肥満症、動脈硬化症、炎症性皮膚疾患、骨粗鬆症などの諸症状の予防又は治療，又は、HCVウイルス感染症の予防又は治療のための他の既知の有効成分を配合することも可能である。 The medicament of the present invention may be administered with an active ingredient compound represented by the general formula (I) and a pharmacologically acceptable salt thereof, or a solvate thereof or a hydrate thereof. However, in general, it is desirable to administer in the form of a pharmaceutical composition containing the above-mentioned substance, which is an active ingredient, and one or more pharmaceutical additives. As an active ingredient of the medicament of the present invention, two or more of the above substances can be used in combination, and the above pharmaceutical composition includes cancer, diabetes, hyperlipidemia, hypercholesterolemia, hypertension, obesity. It is also possible to incorporate other known active ingredients for the prevention or treatment of various symptoms such as arteriosclerosis, inflammatory skin disease, osteoporosis, or the prevention or treatment of HCV virus infection.
　本発明の医薬組成物の種類は特に限定されず、剤型としては、錠剤、カプセル剤、顆粒剤、散剤、シロップ剤、懸濁剤、座剤、軟膏、クリーム剤、ゲル剤、貼付剤、吸入剤、注射剤等が挙げられる。これらの製剤は常法に従って調製される。また、本発明の医薬組成物は、静脈内、皮内、皮下、経口（例えば、吸入なども含む）、経皮及び経粘膜への投与を含み、治療上適切な投与経路に適合するように製剤化される。非経口、皮内、又は皮下への適用に使用される溶液又は懸濁液には、限定はしないが、注射用の水などの滅菌的希釈液、生理食塩水溶液、不揮発性油、ポリエチレングリコール、グリセリン、プロピレングリコール、又は他の合成溶媒、ベンジルアルコール又は他のメチルパラベンなどの保存剤、アスコルビン酸又は亜硫酸水素ナトリウムなどの抗酸化剤、塩化ベンザルコニウム、塩酸プロカインなどの無痛化剤、エチレンジアミンテトラ酢酸（ＥＤＴＡ）などのキレート剤、酢酸塩、クエン酸塩、又はリン酸塩などの緩衝剤、塩化ナトリウム又はデキストロースなど浸透圧調製のための薬剤が含まれていてもよい。 The type of the pharmaceutical composition of the present invention is not particularly limited, and dosage forms include tablets, capsules, granules, powders, syrups, suspensions, suppositories, ointments, creams, gels, patches, Examples include inhalants and injections. These preparations are prepared according to a conventional method. The pharmaceutical composition of the present invention includes intravenous, intradermal, subcutaneous, oral (including inhalation and the like), transdermal and transmucosal administration, and is adapted to a therapeutically appropriate route of administration. Formulated. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application include, but are not limited to, sterile diluents such as water for injection, saline solutions, non-volatile oils, polyethylene glycols, Glycerin, propylene glycol, or other synthetic solvents, benzyl alcohol or other preservatives such as methylparaben, antioxidants such as ascorbic acid or sodium bisulfite, soothing agents such as benzalkonium chloride, procaine hydrochloride, ethylenediaminetetraacetic acid A chelating agent such as (EDTA), a buffering agent such as acetate, citrate, or phosphate, and a drug for osmotic pressure adjustment such as sodium chloride or dextrose may be included.
　液体製剤にあっては、用時、水又は他の適当な溶媒に溶解又は懸濁する形であってもよい。
　また、錠剤、顆粒剤は周知の方法でコーティングしてもよい。
　注射剤の場合には、本発明の化合物を水に溶解させて調製されるが、必要に応じて生理食塩水あるいはブドウ糖溶液に溶解させてもよく、また緩衝剤や保存剤を添加してもよい。
　経口投与用又は非経口投与用の任意の製剤形態で提供される。例えば、顆粒剤、細粒剤、散剤、硬カプセル剤、軟カプセル剤、シロップ剤、乳剤、懸濁剤又は液剤等の形態の経口投与用医薬組成物、静脈内投与用、筋肉内投与用、若しくは皮下投与用などの注射剤、点滴剤、経皮吸収剤、経粘膜吸収剤、点鼻剤、吸入剤、坐剤などの形態の非経口投与用医薬組成物として調製することができる。注射剤や点滴剤などは、凍結乾燥形態などの粉末状の剤形として調製し、用時に生理食塩水などの適宜の水性媒体に溶解して用いることもできる。また、高分子などで被覆した徐放製剤を脳内に直接投与することも可能である。 Liquid preparations may be dissolved or suspended in water or other suitable solvent when used.
Tablets and granules may be coated by a known method.
In the case of injection, it is prepared by dissolving the compound of the present invention in water, but it may be dissolved in physiological saline or glucose solution as necessary, and a buffer or preservative may be added. Good.
It is provided in any dosage form for oral or parenteral administration. For example, a pharmaceutical composition for oral administration in the form of granules, fine granules, powders, hard capsules, soft capsules, syrups, emulsions, suspensions or liquids, for intravenous administration, for intramuscular administration, Alternatively, it can be prepared as a pharmaceutical composition for parenteral administration in the form of injections, drops, transdermal absorbents, transmucosal absorbents, nasal drops, inhalants, suppositories, etc. for subcutaneous administration. Injections, infusions, and the like can be prepared as powdered dosage forms such as freeze-dried forms, and can be used by dissolving in an appropriate aqueous medium such as physiological saline at the time of use. It is also possible to administer a sustained release preparation coated with a polymer directly into the brain.
　医薬組成物の製造に用いられる製剤用添加物の種類、有効成分に対する製剤用添加物の割合、又は医薬組成物の製造方法は、組成物の形態に応じて当業者が適宜選択することが可能である。製剤用添加物としては無機又は有機物質あるいは固体又は液体の物質を用いることができ、一般的には、有効成分重量に対して１重量％から９０重量％の間で配合することができる。具体的には、その様な物質の例として乳糖、ブドウ糖、マンニット、デキストリン、シクロデキストリン、デンプン、蔗糖、メタケイ酸アルミン酸マグネシウム、合成ケイ酸アルミニウム、カルボキシメチルセルロースナトリウム、ヒドロキシプロピルデンプン、カルボキシメチルセルロースカルシウム、メチルセルロース、ゼラチン、アラビアゴム、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、ポリビニルアルコール、軽質無水ケイ酸、ステアリン酸マグネシウム、タルク、トラガント、ベントナイト、ビーガム、酸化チタン、ソルビタン脂肪酸エステル、ラウリル硫酸ナトリウム、グリセリン、脂肪酸グリセリンエステル、精製ラノリン、グリセロゼラチン、ポリソルベート、マクロゴール、植物油、ロウ、流動パラフィン、白色ワセリン、フルオロカーボン、非イオン性界面活性剤、プロピレングルコール、水等が挙げられる。 A person skilled in the art can appropriately select the type of pharmaceutical additive used for the production of the pharmaceutical composition, the ratio of the pharmaceutical additive to the active ingredient, or the method for producing the pharmaceutical composition depending on the form of the composition. It is. As the additive for preparation, an inorganic or organic substance, or a solid or liquid substance can be used, and generally it can be blended in an amount of 1 to 90% by weight based on the weight of the active ingredient. Specifically, examples of such substances are lactose, glucose, mannitol, dextrin, cyclodextrin, starch, sucrose, magnesium aluminate metasilicate, synthetic aluminum silicate, sodium carboxymethylcellulose, hydroxypropyl starch, carboxymethylcellulose calcium. , Methylcellulose, gelatin, gum arabic, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, light anhydrous silicic acid, magnesium stearate, talc, tragacanth, bentonite, bee gum, titanium oxide, sorbitan fatty acid ester, sodium lauryl sulfate, Glycerin, fatty acid glycerin ester, purified lanolin, glycerogelatin, polysorbate, macro Lumpur, vegetable oils, waxes, liquid paraffin, white petrolatum, fluorocarbons, nonionic surfactants, propylene glycol, water and the like.
　経口投与用の固形製剤を製造するには、有効成分と賦形剤成分例えば乳糖、澱粉、結晶セルロース、乳酸カルシウム、無水ケイ酸などと混合して散剤とするか、さらに必要に応じて白糖、ヒドロキシプロピルセルロース、ポリビニルピロリドンなどの結合剤、カルボキシメチルセルロース、カルボキシメチルセルロースカルシウムなどの崩壊剤などを加えて湿式又は乾式造粒して顆粒剤とする。錠剤を製造するには、これらの散剤及び顆粒剤をそのまま或いはステアリン酸マグネシウム、タルクなどの滑沢剤を加えて打錠すればよい。これらの顆粒又は錠剤はヒドロキシプロピルメチルセルロースフタレート、メタクリル酸－メタクリル酸メチルポリマーなどの腸溶剤基剤で被覆して腸溶剤製剤あるいはエチルセルロース、カルナウバロウ、硬化油などで被覆して持続性製剤とすることもできる。また、カプセル剤を製造するには、散剤又は顆粒剤を硬カプセルに充填するか、有効成分をそのまま或いはグリセリン、ポリエチレングリコール、ゴマ油、オリーブ油などに溶解した後ゼラチン膜で被覆し軟カプセルとすることができる。 In order to produce a solid preparation for oral administration, an active ingredient and excipient components such as lactose, starch, crystalline cellulose, calcium lactate, anhydrous silicic acid and the like are mixed to form a powder, or if necessary, sucrose, Add a binder such as hydroxypropylcellulose and polyvinylpyrrolidone, a disintegrant such as carboxymethylcellulose and carboxymethylcellulose calcium, and wet or dry granulate to form granules. In order to produce tablets, these powders and granules may be tableted as they are or after adding a lubricant such as magnesium stearate or talc. These granules or tablets may be coated with an enteric solvent base such as hydroxypropylmethylcellulose phthalate or methacrylic acid-methyl methacrylate polymer and coated with an enteric solvent preparation or ethylcellulose, carnauba wax, hardened oil, etc. to form a sustained preparation. it can. In order to produce capsules, powders or granules are filled into hard capsules, or active ingredients are dissolved as they are or dissolved in glycerin, polyethylene glycol, sesame oil, olive oil, etc., and then coated with a gelatin film to form soft capsules. Can do.
　注射剤を製造するには、有効成分を必要に応じて塩酸、水酸化ナトリウム、乳糖、乳酸、ナトリウム、リン酸一水素ナトリウム、リン酸二水素ナトリウムなどのｐＨ調整剤、塩化ナトリウム、ブドウ糖などの等張化剤と共に注射用蒸留水に溶解し、無菌濾過してアンプルに充填するか、更にマンニトール、デキストリン、シクロデキストリン、ゼラチンなどを加えて真空凍結乾燥し、用事溶解型の注射剤としてもよい。また、有効成分にレチシン、ポリソルベート８０ 、ポリオキシエチレン硬化ヒマシ油などを加えて水中で乳化せしめ注射剤用乳剤とすることもできる。 In order to produce injections, active ingredients such as hydrochloric acid, sodium hydroxide, lactose, lactic acid, sodium, sodium monohydrogen phosphate, sodium dihydrogen phosphate, etc. Dissolve in distilled water for injection together with an isotonic agent, filter aseptically and fill into ampoules, or add mannitol, dextrin, cyclodextrin, gelatin, etc. . In addition, reticine, polysorbate 80, polyoxyethylene hydrogenated castor oil and the like can be added to the active ingredient and emulsified in water to give an emulsion for injection.
　直腸投与剤を製造するには、有効成分をカカオ脂、脂肪酸のトリ、ジ及びモノグリセリド、ポリエチレングリコールなどの座剤用基材と共に加湿して溶解し型に流し込んで冷却するか、有効成分をポリエチレングリコール、大豆油などに溶解した後、ゼラチン膜で被覆すればよい。 To produce a rectal dosage form, the active ingredient is moistened with a suppository base material such as cacao butter, fatty acid tri, di- and monoglycerides, polyethylene glycol, etc., dissolved, poured into a mold and cooled, or the active ingredient is made of polyethylene. What is necessary is just to coat | cover with a gelatin film | membrane after melt | dissolving in glycol, soybean oil, etc.
　本発明の医薬の投与量及び投与回数は特に限定されず、治療対象疾患の悪化・進展の防止及び／又は治療の目的、疾患の種類、患者の体重や年齢、疾患の重篤度などの条件に応じて、医師の判断により適宜選択することが可能である。一般的には、経口投与における成人一日あたりの投与量は０．０１～１０００ｍｇ（有効成分重量）程度であり、一日１回又は数回に分けて、或いは数日ごとに投与することができる。注射剤として用いる場合には、成人に対して一日量０．００１～１００ｍｇ（有効成分重量）を連続投与又は間欠投与することが望ましい。 The dose and frequency of administration of the medicament of the present invention are not particularly limited, and conditions such as prevention and / or progression of the disease to be treated and / or purpose of treatment, type of disease, patient weight and age, severity of the disease, etc. Depending on the situation, it is possible to make an appropriate selection based on the judgment of the doctor. In general, the dose per day for an adult in oral administration is about 0.01 to 1000 mg (weight of active ingredient) and can be administered once or several times a day or every few days. it can. When used as an injection, daily dosages of 0.001 to 100 mg (active ingredient weight) are preferably administered continuously or intermittently to adults.
　本発明の医薬は、植込錠及びマイクロカプセルに封入された送達システムなどの徐放性製剤として、体内から即時に除去されることを防ぎ得る担体を用いて調製することができる。担体として、例えば、エチレンビニル酢酸塩、ポリ酸無水物、ポリグリコール酸、コラーゲン、ポリオルトエステル、及びポリ乳酸などの、生物分解性、生物適合性ポリマーを用いることができる。このような材料は、当業者によって容易に調製することができる。また、リポソームの懸濁液も薬剤的に受容可能な担体として使用することができる。有用なリポソームは、限定はしないが、ホスファチジルコリン、コレステロール及びＰＥＧ誘導ホスファチジルエタノール（ＰＥＧ－ＰＥ）を含む脂質組成物として、使用に適するサイズになるように、適当なポアサイズのフィルターを通して調製され、逆相蒸発法によって精製される。 The medicament of the present invention can be prepared as a sustained-release preparation such as a delivery system encapsulated in implantable tablets and microcapsules, using a carrier that can prevent immediate removal from the body. As the carrier, for example, biodegradable and biocompatible polymers such as ethylene vinyl acetate, polyanhydride, polyglycolic acid, collagen, polyorthoester, and polylactic acid can be used. Such materials can be readily prepared by those skilled in the art. Liposome suspensions can also be used as pharmaceutically acceptable carriers. Useful liposomes are prepared as a lipid composition comprising, but not limited to, phosphatidylcholine, cholesterol and PEG-derivatized phosphatidylethanol (PEG-PE) through a filter of appropriate pore size so as to be suitable for use, and in reverse phase. Purified by evaporation.
　本発明の医薬は、医薬組成物としてキットの形態で、容器、パック中に投与の説明書と共に含めることができる。本発明の医薬組成物がキットとして供給される場合、該組成物のうち異なる構成成分が別々の容器中に包装され、使用直前に混合される。このように構成成分を別々に包装するのは、活性構成成分の機能を失うことなく長期間の貯蔵を可能にするためである。
　キット中に含まれる試薬は、構成成分の活性を長期間有効に持続し、容器内側に吸着することなく、また、構成成分を変質することのない材質で製造された容器中に供給される。例えば、封着されたガラスアンプルは、窒素ガスのような中性で不反応性を示すガスの存在下で封入されたバッファーなどを含んでもよい。アンプルは、ガラス、ポリカーボネート、ポリスチレンなどの有機ポリマー、セラミック、金属、又は試薬を保持するために通常用いられる他の何れかの適切な材料によって構成される。 The medicament of the present invention can be included as a pharmaceutical composition in the form of a kit together with instructions for administration in a container or pack. When the pharmaceutical composition of the present invention is supplied as a kit, different components of the composition are packaged in separate containers and mixed immediately before use. The reason why the components are packaged separately in this way is to enable long-term storage without losing the function of the active component.
The reagent contained in the kit is supplied into a container made of a material that maintains the activity of the component effectively for a long period of time, does not adsorb inside the container, and does not alter the component. For example, a sealed glass ampoule may include a buffer sealed in the presence of a neutral and non-reactive gas such as nitrogen gas. The ampoule is composed of glass, polycarbonate, organic polymers such as polystyrene, ceramic, metal, or any other suitable material commonly used to hold reagents.
　また、キットには使用説明書が添付されてもよい。本キットの使用説明は、紙などに印刷され、及び／又はフロッピー（登録商標）ディスク、ＣＤ－ＲＯＭ、ＤＶＤ－ＲＯＭ、、ビデオテープ、オーディオテープなどの電気的又は電磁的に読み取り可能な媒体に保存されて使用者に供給されてもよい。詳細な使用説明は、キット内に実際に添付されていてもよく、あるいは、キットの製造者又は分配者によって指定され又は電子メール等で通知されるウェブサイトに掲載されていてもよい。 Also, instructions for use may be attached to the kit. Instructions for use of this kit are printed on paper and / or on electrically or electromagnetically readable media such as floppy disks, CD-ROMs, DVD-ROMs, videotapes, audiotapes, etc. It may be stored and supplied to the user. Detailed instructions for use may be actually attached to the kit, or may be posted on a website designated by the manufacturer or distributor of the kit or notified by e-mail or the like.
　さらに、本発明には、ＰＰＡＲα、ＰＰＡＲβ／δ、及び／又はＰＰＡＲγの転写活性の異常（亢進）に起因する疾患（例えば、種々の組織に発症した癌、炎症性皮膚疾患、高脂血症、高コレステロール症、高血圧症、肥満症、動脈硬化症、糖尿病、骨組織の形成不良あるいは骨形成速度よりも骨吸収速度が高くなるなど骨組織形成及び吸収のバランスが崩れることにより発症する疾患（例えば、骨粗鬆症など）など）、又は、ＰＰＡＲα、ＰＰＡＲβ／δ、及び／又はＰＰＡＲγが関与していると考えられているHCVウイルスの感染により発症する疾患の治療方法又は予防方法が含まれる。
　ここで「治療」とは、ＰＰＡＲα、ＰＰＡＲβ／δ、及び／又はＰＰＡＲγ転写活性の異常に起因して発症する疾患等に罹患した哺乳動物において、その病態の進行及び悪化を阻止又は緩和することを意味し、これによって該疾患の進行及び悪化を阻止又は緩和することを目的とする処置のことである。
　また、「予防」とは、ＰＡＲα、ＰＰＡＲβ／δ、及び／又はＰＰＡＲγ転写活性の異常に起因して発症する疾患等に罹患するおそれがある哺乳動物について、該疾患の発症又は罹患を予め阻止することを意味し、これによって該疾患の諸症状等の発症を予め阻止することを目的とする処置のことである。
　治療の対象となる「哺乳動物」は、哺乳類に分類される任意の動物を意味し、特に限定はしないが、例えば、ヒトの他、イヌ、ネコ、ウサギなどのペット動物、ウシ、ブタ、ヒツジ、ウマなどの家畜動物などのことである。特に好ましい「哺乳動物」は、ヒトである。 Furthermore, the present invention includes diseases caused by abnormal (enhanced) transcriptional activity of PPARα, PPARβ / δ, and / or PPARγ (eg, cancer that has developed in various tissues, inflammatory skin diseases, hyperlipidemia, Hypercholesterolemia, hypertension, obesity, arteriosclerosis, diabetes mellitus, diseases that develop due to the imbalance of bone tissue formation and resorption such as bone tissue formation failure or bone resorption rate higher than bone formation rate (for example, , Osteoporosis, etc.), or a method for treating or preventing a disease caused by infection with an HCV virus that is thought to involve PPARα, PPARβ / δ, and / or PPARγ.
Here, “treatment” refers to preventing or alleviating the progression and worsening of the pathological condition in mammals suffering from diseases that develop due to abnormal PPARα, PPARβ / δ, and / or PPARγ transcriptional activity. It means a treatment aimed at preventing or alleviating the progression and worsening of the disease.
In addition, “prevention” refers to blocking in advance the onset or illness of a mammal that may be affected by a disease that develops due to abnormal PARα, PPARβ / δ, and / or PPARγ transcriptional activity. This is a treatment aimed at preliminarily preventing the onset of various symptoms of the disease.
The “mammal” to be treated means any animal classified as a mammal, and is not particularly limited. For example, in addition to humans, pet animals such as dogs, cats, rabbits, cows, pigs, sheep , Livestock animals such as horses. Particularly preferred “mammals” are humans.
　以下に実施例を示してさらに詳細に説明するが、本発明は実施例により何ら限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to the examples.
〔合成例１〕Ｎ―（５－（３－フェニルプロピオルアミド）－２－プロポキシベンジル）－４－（ピリミジン－２－イル）ベンズアミド（化合物１）の合成
５－ニトロ－２－プロポキシベンズアルデヒド
Figure JPOXMLDOC01-appb-C000018
 300mlナス型フラスコに、3.34g(20mmol)の２－ヒドロキシ－５－ニトロベンズアルデヒド、3.31g（24mmol）の炭酸カリウム、2.34g（24mmol）のヨードプロパン、50ml　Ｎ，Ｎ－ジメチルホルムアミドを入れ、80℃で一晩撹拌した。反応液に300mlの 1mol/L　NaOHを入れ、析出した個体を吸引濾過した。酢酸エチルに再び溶解させ、MgSO4で脱水した後に濾過、減圧濃縮し表題化合物を3.36g（収率87%）を得た。 [Synthesis Example 1] Synthesis of N- (5- (3-phenylpropiolamido) -2-propoxybenzyl) -4- (pyrimidin-2-yl) benzamide (Compound 1)
5-Nitro-2-propoxybenzaldehyde
Figure JPOXMLDOC01-appb-C000018
 Into a 300 ml eggplant-shaped flask was placed 3.34 g (20 mmol) 2-hydroxy-5-nitrobenzaldehyde, 3.31 g (24 mmol) potassium carbonate, 2.34 g (24 mmol) iodopropane, 50 ml N, N-dimethylformamide, Stir overnight at ° C. 300 ml of 1 mol / L NaOH was added to the reaction solution, and the precipitated solid was suction filtered. It was dissolved again in ethyl acetate, dehydrated with MgSO 4 , filtered and concentrated under reduced pressure to obtain 3.36 g (yield 87%) of the title compound.
（５－ニトロ－２－プロポキシフェニル）メタンアミン　ＨＣｌ
Figure JPOXMLDOC01-appb-C000019
 100ml ナス型フラスコに、3.5g(16.7mmol)の５－ニトロ－２－プロポキシベンズアルデヒド、4.89g(41.8mmol)のｔ－ブチルカルバメート、8.0ml(50.1mmol)のトリエチルシラン、3.8ml（50.1mmol）のトリフルオロ酢酸、30ml アセトニトリルを入れ、一晩撹拌した。反応液を濃縮し、残留物に30ml 4mol/L　塩酸/酢酸エチルを加え、3時間撹拌した。反応液を濃縮し、酢酸エチルを加え、吸引濾過し,表題化合物4.66g（定量的）を得た。 (5-Nitro-2-propoxyphenyl) methanamine HCl
Figure JPOXMLDOC01-appb-C000019
 In a 100 ml eggplant-shaped flask, 3.5 g (16.7 mmol) 5-nitro-2-propoxybenzaldehyde, 4.89 g (41.8 mmol) t-butyl carbamate, 8.0 ml (50.1 mmol) triethylsilane, 3.8 ml (50.1 mmol) Of trifluoroacetic acid and 30 ml acetonitrile were added and stirred overnight. The reaction mixture was concentrated, 30 ml 4 mol / L hydrochloric acid / ethyl acetate was added to the residue, and the mixture was stirred for 3 hr. The reaction mixture was concentrated, ethyl acetate was added, and suction filtration was performed to obtain 4.66 g (quantitative) of the title compound.
Ｎ－（５－ニトロ－２－プロポキシベンジル）－４－（ピリミジン－２－イル）ベンズアミド
Figure JPOXMLDOC01-appb-C000020
 100mlナス型フラスコに、2.0g(8.13mmol)の４－(ピリミジン－２－イル)安息香酸、1.87g（9.76mmol）のEDCI・HCl、2.48g(20.33mmol)の DMAP、30mlＮ，Ｎ－ジメチルホルムアミドを入れ、一晩撹拌した。反応液を300ml水に入れ、析出した個体を吸引濾過した。残留物を50ml 1mol/L HCl、50ml 飽和炭酸水素トリウム水素溶液、50ml 水の順で洗浄した。酢酸エチルで溶解させ、MgSO4で脱水した後に濾過、減圧濃縮した。残留物に酢酸エチルを加え、析出した個体を吸引濾過し、表題化合物2.80g（収率88%）を得た。 N- (5-nitro-2-propoxybenzyl) -4- (pyrimidin-2-yl) benzamide
Figure JPOXMLDOC01-appb-C000020
 In a 100 ml eggplant-shaped flask, 2.0 g (8.13 mmol) 4- (pyrimidin-2-yl) benzoic acid, 1.87 g (9.76 mmol) EDCI.HCl, 2.48 g (20.33 mmol) DMAP, 30 ml N, N-dimethyl Formamide was added and stirred overnight. The reaction solution was put into 300 ml water, and the precipitated solid was suction filtered. The residue was washed with 50 ml 1 mol / L HCl, 50 ml saturated sodium hydrogen carbonate solution, and 50 ml water in this order. The residue was dissolved in ethyl acetate, dried over MgSO 4 , filtered and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the precipitated solid was subjected to suction filtration to obtain 2.80 g (yield 88%) of the title compound.
Ｎ－（５－アミノ－２－プロポキシベンジル）－４－（ピリミジン－２－イル）ベンズアミド
Figure JPOXMLDOC01-appb-C000021
 300ml　耐圧反応管に、500mg(1.27mmol)のＮ－（５－ニトロ－２－プロポキシベンジル）－４－（ピリミジン－２－イル）ベンズアミド、250mgの10%パラジウム炭素、100ml 酢酸エチル、50ml メタノールを入れ、水素圧0.4MPaで接触還元を行った。セライト濾過でパラジウムを除いて、濾液を濃縮し表題化合物455mg（収率98％）を得た。 N- (5-amino-2-propoxybenzyl) -4- (pyrimidin-2-yl) benzamide
Figure JPOXMLDOC01-appb-C000021
 In a 300 ml pressure-resistant reaction tube, 500 mg (1.27 mmol) N- (5-nitro-2-propoxybenzyl) -4- (pyrimidin-2-yl) benzamide, 250 mg 10% palladium carbon, 100 ml ethyl acetate, 50 ml methanol Then, catalytic reduction was performed at a hydrogen pressure of 0.4 MPa. The palladium was removed by Celite filtration, and the filtrate was concentrated to obtain 455 mg (yield 98%) of the title compound.
Ｎ―（５－（３－フェニルプロピオルアミド）－２－プロポキシベンジル）－４－（ピリミジン－２－イル）ベンズアミド
Figure JPOXMLDOC01-appb-C000022
 50mlナス型フラスコに、50mg(0.138mmol)のＮ－（５－アミノ－２－プロポキシベンジル）－４－（ピリミジン－２－イル）ベンズアミド、24mg(0.165mmol)のフェニルプロピオール酸、63mg(0.165mmol)のＯ－（７－アザベンゾトリアゾール－１－イル）－Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルウロニウムヘキサフルオロホスファート、0.07ml(0.414mmol)の DIEA、10mlのＮ，Ｎ－ジメチルホルムアミドを入れ一晩撹拌した。反応液を100ml水に入れ、析出した固体を吸引濾過し、酢酸エチルで再び溶解した。MgSO4で脱水した後に、残留物をシリカゲルカラムクロマトグラフィー（n-Hexane：AcOEt＝1：1　v/v）にて精製し、表題化合物を26mg（収率38％）得た。
１H-NMR　（CDCl3）δ: 10.72 (s, 1H), 9.05 (t, J = 5.8 Hz, 1H), 8.96 (d, J = 4.8 Hz, 2H), 8.50 (d, J = 8.8 Hz, 2H), 8.09 (d, J = 8.8 Hz, 2H), 7.65-7.59 (m, 3H), 7.53-7.43 (m, 5H), 6.97 (d, J = 9.2 Hz, 1H), 4.48 (d, J = 5.6 Hz, 2H), 3.98 (t, J = 6.4 Hz, 2H), 1.80-1.75 (m, 2H), 1.02 (t, J = 7.2 Hz, 3H). N- (5- (3-Phenylpropiolamido) -2-propoxybenzyl) -4- (pyrimidin-2-yl) benzamide
Figure JPOXMLDOC01-appb-C000022
 In a 50 ml eggplant-shaped flask, 50 mg (0.138 mmol) N- (5-amino-2-propoxybenzyl) -4- (pyrimidin-2-yl) benzamide, 24 mg (0.165 mmol) phenylpropiolic acid, 63 mg (0.165 mmol) O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate, 0.07 ml (0.414 mmol) DIEA, 10 ml N, N- Dimethylformamide was added and stirred overnight. The reaction solution was put into 100 ml of water, and the precipitated solid was subjected to suction filtration and dissolved again with ethyl acetate. After dehydration with MgSO 4 , the residue was purified by silica gel column chromatography (n-Hexane: AcOEt = 1: 1 v / v) to obtain 26 mg (yield 38%) of the title compound.
1 H-NMR (CDCl3) δ: 10.72 (s, 1H), 9.05 (t, J = 5.8 Hz, 1H), 8.96 (d, J = 4.8 Hz, 2H), 8.50 (d, J = 8.8 Hz, 2H ), 8.09 (d, J = 8.8 Hz, 2H), 7.65-7.59 (m, 3H), 7.53-7.43 (m, 5H), 6.97 (d, J = 9.2 Hz, 1H), 4.48 (d, J = 5.6 Hz, 2H), 3.98 (t, J = 6.4 Hz, 2H), 1.80-1.75 (m, 2H), 1.02 (t, J = 7.2 Hz, 3H).
　化合物１と同様にして、下記の式（Ｉｂ）で表される新規アセチレンアミド誘導体（化合物２～化合物１６）を合成した。
Figure JPOXMLDOC01-appb-C000023
 　また、化合物１７～２７についても、スキーム１に従い、ｃ工程及びｅ工程で、所望のカルボン酸を選択して合成を行った。 In the same manner as Compound 1, novel acetylenamide derivatives (Compound 2 to Compound 16) represented by the following formula (Ib) were synthesized.
Figure JPOXMLDOC01-appb-C000023
 Compounds 17 to 27 were also synthesized according to Scheme 1 by selecting the desired carboxylic acid in steps c and e.
　化合物２～２７を表１～表４に列挙し、表５及び表６にその物理化学データを示す。
Figure JPOXMLDOC01-appb-T000024
 Compounds 2 to 27 are listed in Tables 1 to 4, and Tables 5 and 6 show the physicochemical data.
Figure JPOXMLDOC01-appb-T000024
Figure JPOXMLDOC01-appb-T000025
Figure JPOXMLDOC01-appb-T000025
Figure JPOXMLDOC01-appb-T000026
Figure JPOXMLDOC01-appb-T000026
Figure JPOXMLDOC01-appb-T000027
Figure JPOXMLDOC01-appb-T000027
Figure JPOXMLDOC01-appb-T000028
Figure JPOXMLDOC01-appb-T000028
Figure JPOXMLDOC01-appb-T000029
Figure JPOXMLDOC01-appb-T000029
〔実験例〕
１．本発明化合物のＰＰＡＲα、ＰＰＡＲβ／δ、ＰＰＡＲγアンタゴニスト活性の測定
　１０％脱脂牛血清を含むダルベッコ変法イ－グル培地（ＦＣＳ／ＤＭＥＭ）にて培養したヒト胎児腎細胞（ＨＥＫ２９３）（化合物１～１６）、又は、アフリカミドリザル腎細胞（ＣＯＳ－１）（化合物１７～２７）に、酵母の転写因子（ＧＡＬ４）のＤＮＡ結合領域とヒト型ＰＰＡＲγのリガンド結合領域との融合蛋白質を発現する受容体プラスミド及びそのレポータープラスミド、さらに内部標準用のβガラクトシダーゼプラスミドを、リン酸カルシウム法により（化合物１～１６）、又はX-tremegene9（Roche社）を使用して（化合物１７～２７）コトランスフェクションした。その後、被検化合物およびＰＰＡＲパンアゴニストであるTIPP-703を添加して１６時間後（化合物１～１６）、又は、２４時間後（化合物１７～２７）にルシフェラ－ゼ活性ならびにβガラクトシダーゼ活性を測定し、内部標準により補正した。
　上記方法により測定したＰＰＡＲα、ＰＰＡＲβ／δ、ＰＰＡＲγに対するIＣ５０の値を表７に示す。なお、表中N.T.はnot testedを示し、N.D.はnot determinedを示す。 [Experimental example]
1. Measurement of PPARα, PPARβ / δ, PPARγ antagonist activity of the compound of the present invention Human embryonic kidney cells (HEK293) cultured in Dulbecco's modified Eagle's medium (FCS / DMEM) containing 10% defatted bovine serum (compounds 1 to 16) ) Or a receptor plasmid that expresses a fusion protein of a yeast transcription factor (GAL4) DNA binding region and a human PPARγ ligand binding region in African green monkey kidney cells (COS-1) (compounds 17 to 27) And its reporter plasmid, and β-galactosidase plasmid for internal standard were co-transfected by the calcium phosphate method (compounds 1-16) or using X-tremegene9 (Roche) (compounds 17-27). Thereafter, luciferase activity and β-galactosidase activity are measured 16 hours after addition of the test compound and TIPP-703 which is a PPAR pan agonist (compounds 1 to 16) or 24 hours (compounds 17 to 27). Corrected by the internal standard.
Table 7 shows the IC 50 values for PPARα, PPARβ / δ, and PPARγ measured by the above method. In the table, NT indicates not tested, and ND indicates not determined.
Figure JPOXMLDOC01-appb-T000030
 　表７に示すように、本発明の化合物１～１６は、ＰＰＡＲγに対するアンタゴニストとして作用することが明かとなった。特に、式（Ｉｂ）のＲ４がフェニル基の場合にその２位の位置に置換基等を有する化合物（化合物１３の他、化合物２、１５、１６など）、及び、Ｒ４がピリミジン－２―イル基のようにベンゼン環の２位が窒素等である化合物（化合物１２）には、アゴニスト活性がほとんど認められなかったことから（データは示さず）、このような化合物は、強力なＰＰＡＲγに選択的なアンタゴニストであると考えられる。
　化合物１７～２７については、ＰＰＡＲα、ＰＰＡＲβ／δ及びＰＰＡＲγに対するアンタゴニスト活性を有していることが確認された。
Figure JPOXMLDOC01-appb-T000030
 As shown in Table 7, it has been clarified that the compounds 1 to 16 of the present invention act as antagonists for PPARγ. In particular, when R 4 in formula (Ib) is a phenyl group, a compound having a substituent or the like at the 2-position thereof (compound 13, as well as compounds 2, 15, 16, etc.), and R 4 is pyrimidine-2 -Since the compound (compound 12) in which the 2-position of the benzene ring is nitrogen or the like as in the yl group has almost no agonist activity (data not shown), such a compound has a strong PPARγ Are considered to be selective antagonists.
Compounds 17 to 27 were confirmed to have antagonist activity against PPARα, PPARβ / δ and PPARγ.
２．本発明のＰＰＡＲγアンタゴニスト（化合物１～１６）と既存のＰＰＡＲγアンタゴニストとの作用機序の比較
２－１．比較１
　既存のＰＰＡＲγアンタゴニストであるGW9662との作用機序に違いがあるか検討した。具体的には、ＰＰＡＲγを不活性化する効果に違いがあるか調べる為にＰＰＡＲγとコリプレッサーの相互作用を強める効力について比較を行った。一般的にＰＰＡＲγとコリプレッサーが相互作用するほど、ＰＰＡＲγは不活性化する効果が高いことが知られている（J Biol Chem. 2005 Apr 8;280(14):13600-5.）。
　１０％牛胎児血清を含むダルベッコ変法イ－グル培地（ＦＢＳ／ＤＭＥＭ）にて培養したアフリカミドリザル腎細胞（ＣＯＳ－１）に、ヘルペスウィルスの活性化ドメイン（ＶＰ１６）とヒト型ＮＣｏＲとの融合蛋白質を発現するプラスミドと酵母の転写因子（ＧＡＬ４）のＤＮＡ結合領域とヒト型ＰＰＡＲγのリガンド結合領域との融合蛋白質を発現する受容体プラスミド及びそのレポータープラスミド、さらに内部標準用の分泌性アルカリホスファターゼ（ＳＥＡＰ）プラスミドをトランスフェクション用試薬であるX-tremegene9を使用しコトランスフェクションした。その後、被検化合物（ピオグリタゾン、GW9662、化合物１２及び化合物１３）を添加して２４時間後にルシフェラ－ゼ活性、並びに、アルカリホスファターゼ活性を測定し、内部標準により補正した。測定の結果を図１に示す。 2. 2. Comparison of action mechanism of PPARγ antagonists of the present invention (compounds 1 to 16) and existing PPARγ antagonists 2-1. Comparison 1
It was examined whether there is a difference in the mechanism of action with the existing PPARγ antagonist GW9662. Specifically, in order to examine whether there is a difference in the effect of inactivating PPARγ, a comparison was made with respect to the efficacy of enhancing the interaction between PPARγ and the corepressor. In general, it is known that PPARγ has a higher inactivation effect as PPARγ and a corepressor interact (J Biol Chem. 2005 Apr 8; 280 (14): 13600-5.).
Fusion of herpesvirus activation domain (VP16) and human NCoR to African green monkey kidney cells (COS-1) cultured in Dulbecco's modified Eagle medium (FBS / DMEM) containing 10% fetal bovine serum A receptor plasmid expressing a fusion protein of a protein-expressing plasmid, a yeast transcription factor (GAL4) DNA-binding region and a human-type PPARγ ligand-binding region, and a reporter plasmid thereof, and a secreted alkaline phosphatase for an internal standard ( The (SEAP) plasmid was co-transfected using X-tremegene9, a transfection reagent. Thereafter, test compounds (pioglitazone, GW9662, compound 12 and compound 13) were added, and luciferase activity and alkaline phosphatase activity were measured 24 hours later and corrected with an internal standard. The measurement results are shown in FIG.
　アゴニストであるピオグリタゾンは、ＰＰＡＲγとコリプレッサーの相互作用を抑制したが、式（Ｉｂ）で表される化合物のうち、化合物１２と化合物１３は、既存のアンタゴニストであるGW9662よりもその相互作用を強めることが明らかとなった。すなわち、化合物１２と化合物１３は、GW9662よりもＰＰＡＲγを不活性化する効力が強いということが明らかとなった。 The agonist pioglitazone suppressed the interaction between PPARγ and the corepressor, but among the compounds represented by the formula (Ib), compound 12 and compound 13 are stronger than the existing antagonist GW9662. It became clear. That is, it has been clarified that Compound 12 and Compound 13 are more potent in inactivating PPARγ than GW9662.
２－２．比較２
　次に、恒常的に活性化している全長ＰＰＡＲγを用いた活性の比較を行った。
　１０％牛胎児血清を含むダルベッコ変法イ－グル培地（ＦＢＳ／ＤＭＥＭ）にて培養したアフリカミドリザル腎細胞（ＣＯＳ－１）に、ヒト型全長ＰＰＡＲγ１を発現する受容体プラスミド及び３ x ＰＰＲＥ（ＰＰＡＲ応答配列）レポータープラスミド、さらに内部標準用の分泌性アルカリホスファターゼ（ＳＥＡＰ）プラスミドをトランスフェクション用試薬であるX-tremegene9を使用しコトランスフェクションした。その後、被検化合物（ピオグリタゾン、GW9662、化合物１２及び化合物１３）を添加して２４時間後にルシフェラ－ゼ活性ならびにアルカリホスファターゼ活性を測定し、内部標準により補正した。測定の結果を図２に示す。 2-2. Comparison 2
Next, the activity was compared using full-length PPARγ that was constantly activated.
An African green monkey kidney cell (COS-1) cultured in Dulbecco's modified Eagle's medium (FBS / DMEM) containing 10% fetal bovine serum was transferred to a receptor plasmid expressing human full-length PPARγ1 and 3 × PPRE (PPAR). Response element) Reporter plasmid, and secretory alkaline phosphatase (SEAP) plasmid for internal standard were co-transfected using X-tremegene9 as a transfection reagent. Thereafter, test compounds (pioglitazone, GW9662, compound 12 and compound 13) were added, and luciferase activity and alkaline phosphatase activity were measured 24 hours later and corrected with an internal standard. The measurement results are shown in FIG.
　アゴニストであるピオグリタゾンは、ＰＰＡＲγ活性を上昇させたが、化合物１、化合物１２及び化合物１３は、GW9662 よりも強くＰＰＡＲγ活性を抑制することが明らかとなった。この結果から、本発明の化合物は、既存のＰＰＡＲγアンタゴニストよりも強くＰＰＡＲγ活性を抑制し、特に、式（Ｉｂ）で表される化合物のうち、Ｒ４の２位に置換基を有する化合物１２や、２位が窒素である化合物１３は、既存のＰＰＡＲγアンタゴニストであるGW9662よりも強くＰＰＡＲγ活性を抑制することが明かとなった。 Pioglitazone, an agonist, increased PPARγ activity, but Compound 1, Compound 12 and Compound 13 were found to suppress PPARγ activity more strongly than GW9662. From this result, the compound of the present invention suppresses PPARγ activity more strongly than the existing PPARγ antagonist, and among the compounds represented by the formula (Ib), in particular, the compound 12 having a substituent at the 2-position of R 4 It became clear that the compound 13 in which the 2-position is nitrogen suppresses PPARγ activity more strongly than GW9662, which is an existing PPARγ antagonist.
３．脂肪細胞分化の抑制作用
３－１．化合物１２の脂肪細胞分化に対する影響の検討
　本発明の下記の化合物１２を用いて、脂肪細胞への分化過程に対し、どのような影響を及ぼすか検討を行った。
Figure JPOXMLDOC01-appb-C000031
 Day0（実験開始日）；
６ウェルプレート中にて、10%BCS DMEM培地で培養したマウス線維芽細胞株3T3-L1がコンフルエントになった後、1μM デキサメタゾン,　0.5mM IBMX, 5μg/mL insulin、DMSO（コントロール）又は各濃度の試験化合物（化合物１２、ピオグリタゾン）を含有する10%FBS DMEM　2mLで各ウェルの培地交換を行った。
Day2；
DMSO又は各濃度の試験化合物を含むDMEM（10%FBS）を各ウェルに1mLずつ添加した（培地添加）。
Day3；
DMSO又は各濃度の試験化合物を含む10%FBS　DMEM　2mLで各ウェルの培地交換を行った．
Day5；
Day3と同じ操作を行った。
Day7；
Day3と同じ操作を行った。
Day9；
oil red O染色（脂肪前駆細胞から脂肪細胞への分化を確認するための染色方法）を行い、染色処理を行った細胞を顕微鏡で観察した。
　脂肪細胞に分化した細胞は、細胞中のトリグリセリドがO染色により赤色に染色される。強く赤色に染色されるほど、脂肪細胞への分化度が大きいことになる。 3. 3. Inhibition of adipocyte differentiation 3-1. Examination of the effect of compound 12 on adipocyte differentiation The following compound 12 of the present invention was used to examine the effect on the differentiation process into adipocytes.
Figure JPOXMLDOC01-appb-C000031
 Day0 (Experiment start date);
After the mouse fibroblast cell line 3T3-L1 cultured in 10% BCS DMEM medium became confluent in a 6-well plate, 1 μM dexamethasone, 0.5 mM IBMX, 5 μg / mL insulin, DMSO (control), or various concentrations The medium was changed in each well with 2 mL of 10% FBS DMEM containing the test compound (Compound 12, Pioglitazone).
Day2;
1 mL of DMSO or DMEM (10% FBS) containing each concentration of test compound was added to each well (medium addition).
Day3;
The medium was changed in each well with 2 mL of DMSO or 10% FBS DMEM containing each concentration of test compound.
Day5;
Same operation as Day3.
Day7;
Same operation as Day3.
Day9;
Oil red O staining (staining method for confirming differentiation from preadipocytes to adipocytes) was performed, and the stained cells were observed with a microscope.
In cells differentiated into adipocytes, triglycerides in the cells are stained red by O staining. The stronger the red staining, the greater the degree of differentiation into adipocytes.
　実験の結果（図３Ａ）、赤色に染まった脂肪細胞（図では暗色）の数は、化合物１２の用量依存的に減少し、10μＭの化合物１２を添加することで、脂肪細胞への分化が完全に阻害されることが明かとなった。
　次に、ＰＰＲＡγアゴニストとして作用し、脂肪細胞の分化を促進することが知られているピオグリタゾンの存在下おける化合物１２の効果を検討した。図３Ｂから、ピオグリタゾンによって用量依存的に誘導された脂肪細胞への誘導が、化合物１２により抑制されることが分かった。 As a result of the experiment (FIG. 3A), the number of fat cells stained in red (dark in the figure) decreased in a dose-dependent manner with Compound 12, and the addition of 10 μM Compound 12 completely differentiated into adipocytes. It became clear that it was disturbed.
Next, the effect of Compound 12 in the presence of pioglitazone, which is known to act as a PPRAγ agonist and promote differentiation of adipocytes, was examined. From FIG. 3B, it was found that the induction into adipocytes induced by pioglitazone in a dose-dependent manner was suppressed by compound 12.
３－２．化合物１３の脂肪細胞分化に対する影響の検討
　次に、本発明の化合物１３を用いて、脂肪細胞への分化過程に対し、どのような影響を及ぼすか検討を行った。
Day0（実験開始日）；
２４ウェルプレート中にて、10%BCS DMEM培地で培養したマウス線維芽細胞株3T3-L1がコンフルエントになった後、5μg/ml インスリン、1μM ピオグリタゾン、DMSO（コントロール）又は各濃度の試験化合物（化合物１３）を含有する10%FBS DMEM、1 mLで各ウェルの培地交換を行った。
Day2；
DMSOまたはピオグリタゾン1μＭと各濃度の試験化合物を含むDMEM（10%FBS）、500μLで各ウェルの培地交換を行った。
Day4；
Day2と同じ操作を行った。
Day6；
Day2と同じ操作を行った。
Day8；
oil red O染色（脂肪前駆細胞から脂肪細胞への分化を確認するための染色方法）を行い、染色後、100%イソプロパノールを添加して、oil red Oを溶出させ、プレートリーダーを用いて、490nmの吸光度を測定した。吸光度が高い程、脂肪細胞への分化が促進されることを示す。結果を図４に示す。 3-2. Examination of influence of compound 13 on adipocyte differentiation Next, using compound 13 of the present invention, the influence on the differentiation process into adipocytes was examined.
Day0 (Experiment start date);
After confluence of mouse fibroblast cell line 3T3-L1 cultured in 10% BCS DMEM medium in a 24-well plate, 5 μg / ml insulin, 1 μM pioglitazone, DMSO (control), or test compound (compound) The medium in each well was replaced with 1 mL of 10% FBS DMEM containing 13).
Day2;
The medium was exchanged in each well with 500 μL of DMEM (10% FBS) containing 1 μM DMSO or pioglitazone and each concentration of the test compound.
Day4;
Same operation as Day 2.
Day6;
Same operation as Day 2.
Day8;
Perform oil red O staining (staining method for confirming differentiation from preadipocytes to adipocytes), and after staining, add 100% isopropanol to elute oil red O and use a plate reader to 490 nm The absorbance was measured. Higher absorbance indicates that differentiation into adipocytes is promoted. The results are shown in FIG.
　ＰＰＡＲγのアゴニストであるピオグリタゾンは、脂肪細胞への分化を強く誘導した（コントロールのDMSOと比較して吸光度が高い）。これに対し、化合物１３は、ピオグリタゾンによる脂肪細胞への誘導をほぼ完全に抑制した。すなわち、化合物１３は、脂肪前駆細胞において、ＰＰＡＲγフルアンタゴニストとして働き、その脂肪細胞への分化を強く抑制した。 Pioglitazone, an agonist of PPARγ, strongly induced differentiation into adipocytes (higher absorbance than control DMSO). In contrast, Compound 13 almost completely suppressed the induction of adipocytes by pioglitazone. That is, Compound 13 acted as a PPARγ full antagonist in preadipocytes, and strongly suppressed its differentiation into adipocytes.
３－３．化合物１３とGW9662の脂肪細胞分化に対する影響の比較
　既存のＰＰＡＲγアンタゴニストであるGW9662と化合物１３の脂肪細胞分化に対する影響を検討した。
　上記３－２の実験と同様に、10%BCS DMEM培地で培養したマウス線維芽細胞株3T3-L1がコンフルエントになった後、1μM ピオグリタゾン存在下において、GE9662と化合物１３を、各々、0.1μM又は1μM添加し、Oil red Oによる染色度を490nmの吸光度を測定することにより評価した。
　その結果、本発明の化合物１３を1μM添加すると、GW9662に比して、非常に強力に、脂肪前駆細胞の脂肪分化を抑制することが明かとなった（図５）。 3-3. Comparison of the effects of Compound 13 and GW9662 on adipocyte differentiation The effects of GW9662 and Compound 13 which are existing PPARγ antagonists on adipocyte differentiation were examined.
Similar to the experiment in 3-2 above, after the mouse fibroblast cell line 3T3-L1 cultured in 10% BCS DMEM medium became confluent, in the presence of 1 μM pioglitazone, GE9662 and Compound 13 were each 0.1 μM or 1 μM was added, and the degree of staining with Oil red O was evaluated by measuring the absorbance at 490 nm.
As a result, it was revealed that when 1 μM of the compound 13 of the present invention was added, the adipogenesis of preadipocytes was suppressed much more strongly than GW9662 (FIG. 5).
　以上の結果から、本発明の化合物１～１６は、ＰＰＡＲγアンタゴニスト活性を有しており、特に、化合物１２と１３は、既存のGW9662と比較して、脂肪細胞への分化誘導を強力に抑制することが明かになった。従って、本発明の化合物は、糖尿病や肥満症等、メタボリックシンドロームの治療剤の有効成分として利用することができる。また、脂肪細胞及び骨芽細胞などは、各々の存在量のバランスを維持しながら、間葉系幹細胞から分化するとの知見、さらに、ＰＰＡＲγアンタゴニストが骨組織の発生を誘導するとの知見などもあり（非特許文献１３）、本発明の化合物が骨粗鬆症などの治療にも利用可能であることが示唆される。 From the above results, the compounds 1 to 16 of the present invention have PPARγ antagonist activity, and in particular, the compounds 12 and 13 strongly suppress the induction of differentiation into adipocytes as compared with the existing GW9662. It became clear. Therefore, the compound of the present invention can be used as an active ingredient of a therapeutic agent for metabolic syndrome such as diabetes and obesity. In addition, there are knowledge that adipocytes and osteoblasts are differentiated from mesenchymal stem cells while maintaining the balance of their abundance, and further knowledge that PPARγ antagonists induce the development of bone tissue ( Non-patent document 13) suggests that the compounds of the present invention can also be used for the treatment of osteoporosis and the like.
　本発明の化合物は、ＰＰＡＲα、ＰＰＡＲβ／δ、ＰＰＡＲγのアンタゴニストの活性を有する。従って、これらの化合物を有効成分として含有する医薬は、ＰＰＡＲの活性異常に起因する疾患の治療等に効果を発揮することが期待される。 The compound of the present invention has PPARα, PPARβ / δ, PPARγ antagonist activity. Therefore, a medicament containing these compounds as an active ingredient is expected to exert an effect on treatment of diseases caused by abnormal PPAR activity.

Claims (16)

  1. 　下記一般式（ I ）：
    Figure JPOXMLDOC01-appb-C000001
     ［式中、Ｒ１は無置換又は置換基を有しても良いフェニル基、ピリミジン－２－イル基、２－ピリジル基、２－チエニル基、ピペリジノ基、シクロヘキシル基、アダマンチル基、トリフルオロメチル基、メトキシ基、フェノキシ基、４－フルオロフェノキシ基、アニリノ基を表し、Ｒ２は水素原子又はフッ素原子を表し、Ｒ３は炭素数１から６の直鎖状又は分岐状アルキル基を表し、Ｒ４は無置換又は置換基を有しても良いフェニル基、炭素数５～７のシクロアルキル基、ピリジル基、チエニル基を表す］で表されるアセチレンアミド誘導体若しくはその薬学上許容される塩又はそれらの水和物。     The following general formula (I):
    Figure JPOXMLDOC01-appb-C000001
     [Wherein R 1 is unsubstituted or optionally substituted phenyl, pyrimidin-2-yl, 2-pyridyl, 2-thienyl, piperidino, cyclohexyl, adamantyl, trifluoromethyl A methoxy group, a phenoxy group, a 4-fluorophenoxy group, an anilino group, R 2 represents a hydrogen atom or a fluorine atom, R 3 represents a linear or branched alkyl group having 1 to 6 carbon atoms, R 4 represents an unsubstituted or optionally substituted phenyl group, a cycloalkyl group having 5 to 7 carbon atoms, a pyridyl group, a thienyl group], or a pharmaceutically acceptable salt thereof. Or their hydrates.
  2. 　Ｒ１がピリミジン－２－イル基、Ｒ２が水素原子、Ｒ３がプロピル基である、請求項１に記載のアセチレンアミド誘導体若しくはその薬学上許容される塩又はそれらの水和物。 The acetylenamide derivative according to claim 1, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, wherein R 1 is a pyrimidin-2-yl group, R 2 is a hydrogen atom, and R 3 is a propyl group.
  3. 　Ｒ４がメチルフェニル基、メトキシフェニル基、フルオロフェニル基、シクロペンチル基、チエニル基、ピリジン－２－イル基、クロロフェニル基、ブロモフェニル基又はトリフルオロメチル基である請求項２に記載のアセチレンアミド誘導体若しくはその薬学上許容される塩又はそれらの水和物。 The acetylenamide derivative according to claim 2, wherein R 4 is a methylphenyl group, a methoxyphenyl group, a fluorophenyl group, a cyclopentyl group, a thienyl group, a pyridin-2-yl group, a chlorophenyl group, a bromophenyl group, or a trifluoromethyl group. Or a pharmaceutically acceptable salt thereof or a hydrate thereof.
  4. 　Ｒ４がフェニル基又は２－チエニル基、Ｒ２が水素原子、Ｒ３がプロピル基である、請求項１に記載のアセチレンアミド誘導体若しくはその薬学上許容される塩又はそれらの水和物。 The acetylene amide derivative according to claim 1, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, wherein R 4 is a phenyl group or 2-thienyl group, R 2 is a hydrogen atom, and R 3 is a propyl group.
  5. 　Ｒ１が、無置換又は置換基を有しても良いフェニル基、２－チエニル基、ピペリジノ基、シクロヘキシル基、トリフルオロメチル基、メトキシ基、フェノキシ基、４－フルオロフェノキシ基又はアニリノ基である、請求項４に記載のアセチレンアミド誘導体若しくはその薬学上許容される塩又はそれらの水和物。 R 1 is an unsubstituted or optionally substituted phenyl group, 2-thienyl group, piperidino group, cyclohexyl group, trifluoromethyl group, methoxy group, phenoxy group, 4-fluorophenoxy group or anilino group. The acetylene amide derivative according to claim 4, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  6. 　一般式（ I ）で表される化合物が、
    Ｎ―（５－（３－フェニルプロピオルアミド）－２－プロポキシベンジル）－４－（ピリミジン－２－イル）ベンズアミド、
    Ｎ－（２－プロポキシ－５－（３－ｏ－トルイルプロピオルアミド）ベンジル）－４－（ピリミジン－２－イル）ベンズアミド、
    Ｎ－（５－（３－（２－クロロフェニル）プロピオルアミド）－２－プロポキシベンジル）－４－（ピリミジン－２－イル）ベンズアミド、
    Ｎ－（２－プロポキシ－５－（３－ピリジン－２－イル）プロピオルアミド）ベンジル）－４－（ピリミジン－２－イル）ベンズアミド］
    ４－（４－フルオロフェノキシ）－Ｎ－（２－プロポキシ－５－（３－（チオフェン－２－イル）プロピオアミド）ベンジル）ベンズアミド
    のいずれかである請求項１に記載のアセチレンアミド誘導体若しくはその薬学上許容される塩又はそれらの水和物。     The compound represented by the general formula (I) is
    N- (5- (3-phenylpropiolamido) -2-propoxybenzyl) -4- (pyrimidin-2-yl) benzamide,
    N- (2-propoxy-5- (3-o-toluylpropiolamido) benzyl) -4- (pyrimidin-2-yl) benzamide,
    N- (5- (3- (2-chlorophenyl) propiolamido) -2-propoxybenzyl) -4- (pyrimidin-2-yl) benzamide,
    N- (2-propoxy-5- (3-pyridin-2-yl) propiolamido) benzyl) -4- (pyrimidin-2-yl) benzamide]
    The acetylenamide derivative according to claim 1, which is any one of 4- (4-fluorophenoxy) -N- (2-propoxy-5- (3- (thiophen-2-yl) propioamido) benzyl) benzamide or a pharmaceutical thereof Top acceptable salts or hydrates thereof.
  7. 　請求項１乃至６のいずれかに記載のアセチレンアミド誘導体若しくはその薬学上許容される塩又はそれらの水和物を含有する、医薬組成物。 A pharmaceutical composition comprising the acetylenamide derivative according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  8. 　癌、糖尿病、肥満症、HCVウイルス感染症、炎症性皮膚疾患、骨組織の形成不良に起因する疾患の治療又は予防のための請求項７に記載の医薬組成物。 The pharmaceutical composition according to claim 7, for the treatment or prevention of cancer, diabetes, obesity, HCV virus infection, inflammatory skin disease, or disease caused by poor bone tissue formation.
  9. 　下記一般式（ I ）表されるＰＰＡＲα、ＰＰＡＲβ／δ、及び／又は、ＰＰＡＲγに対するアンタゴニスト。
    Figure JPOXMLDOC01-appb-C000002
     ［式中、Ｒ１は無置換又は置換基を有しても良いフェニル基、ピリミジン－２－イル基、２－ピリジル基、２－チエニル基、ピペリジノ基、シクロヘキシル基、アダマンチル基、トリフルオロメチル基、メトキシ基、フェノキシ基、４－フルオロフェノキシ基、アニリノ基を表し、Ｒ２は水素原子又はフッ素原子を表し、Ｒ３は炭素数１から６の直鎖状又は分岐状アルキル基を表し、Ｒ４は無置換又は置換基を有しても良いフェニル基、炭素数５～７のシクロアルキル基、ピリジル基、チエニル基を表す］     An antagonist to PPARα, PPARβ / δ, and / or PPARγ represented by the following general formula (I).
    Figure JPOXMLDOC01-appb-C000002
     [Wherein R 1 is unsubstituted or optionally substituted phenyl, pyrimidin-2-yl, 2-pyridyl, 2-thienyl, piperidino, cyclohexyl, adamantyl, trifluoromethyl A methoxy group, a phenoxy group, a 4-fluorophenoxy group, an anilino group, R 2 represents a hydrogen atom or a fluorine atom, R 3 represents a linear or branched alkyl group having 1 to 6 carbon atoms, R 4 represents an unsubstituted or optionally substituted phenyl group, a cycloalkyl group having 5 to 7 carbon atoms, a pyridyl group, or a thienyl group.
  10. 　Ｒ１がピリミジン－２－イル基、Ｒ２が水素原子、Ｒ３がプロピル基である、請求項９に記載のＰＰＡＲγアンタゴニスト。 10. The PPARγ antagonist according to claim 9, wherein R 1 is a pyrimidin-2-yl group, R 2 is a hydrogen atom, and R 3 is a propyl group.
  11. 　Ｒ４がメチルフェニル基、メトキシフェニル基、フルオロフェニル基、シクロペンチル基、チエニル基、ピリジル基、クロロフェニル基、ブロモフェニル基又はトリフルオロメチル基である請求項１０に記載のＰＰＡＲγアンタゴニスト。 The PPARγ antagonist according to claim 10, wherein R 4 is a methylphenyl group, a methoxyphenyl group, a fluorophenyl group, a cyclopentyl group, a thienyl group, a pyridyl group, a chlorophenyl group, a bromophenyl group, or a trifluoromethyl group.
  12. 　Ｒ４が２－クロロフェニル基又はピリジン－２－イル基である請求項１１に記載のＰＰＡＲγアンタゴニスト。 The PPARγ antagonist according to claim 11, wherein R 4 is a 2-chlorophenyl group or a pyridin-2-yl group.
  13. 　Ｒ４がフェニル基又は２－チエニル基、Ｒ２が水素原子、Ｒ３がプロピル基である、請求項９に記載のＰＰＡＲα、ＰＰＡＲβ／δ、及びＰＰＡＲγに対するアンタゴニスト。 The antagonist for PPARα, PPARβ / δ, and PPARγ according to claim 9, wherein R 4 is a phenyl group or 2-thienyl group, R 2 is a hydrogen atom, and R 3 is a propyl group.
  14. 　Ｒ１が、無置換又は置換基を有しても良いフェニル基、２－チエニル基、ピペリジノ基、シクロヘキシル基、トリフルオロメチル基、メトキシ基、フェノキシ基、４－フルオロフェノキシ基又はアニリノ基である、請求項１３に記載のＰＰＡＲα、ＰＰＡＲβ／δ、及びＰＰＡＲγに対するアンタゴニスト。 R 1 is an unsubstituted or optionally substituted phenyl group, 2-thienyl group, piperidino group, cyclohexyl group, trifluoromethyl group, methoxy group, phenoxy group, 4-fluorophenoxy group or anilino group. 14. An antagonist to PPARα, PPARβ / δ, and PPARγ according to claim 13.
  15. 　下記一般式( II )、
    Figure JPOXMLDOC01-appb-C000003
     ［式中、Ｒ１は無置換又は置換基を有しても良いフェニル基、ピリミジン－２－イル基、２－ピリジル基、２－チエニル基、ピペリジノ基、シクロヘキシル基、アダマンチル基、トリフルオロメチル基、メトキシ基、フェノキシ基、４－フルオロフェノキシ基、アニリノ基を表し、Ｒ２は水素原子又はフッ素原子を表し、Ｒ３は炭素数１から６の直鎖状又は分岐状アルキル基を表す］で表される化合物。     The following general formula (II),
    Figure JPOXMLDOC01-appb-C000003
     [Wherein R 1 is unsubstituted or optionally substituted phenyl, pyrimidin-2-yl, 2-pyridyl, 2-thienyl, piperidino, cyclohexyl, adamantyl, trifluoromethyl A methoxy group, a phenoxy group, a 4-fluorophenoxy group, an anilino group, R 2 represents a hydrogen atom or a fluorine atom, and R 3 represents a linear or branched alkyl group having 1 to 6 carbon atoms] A compound represented by
  16. 　下記一般式( II )の化合物と下記一般式( V III )の化合物とを反応させて、下記一般式( I )の化合物を製造する方法。
    Figure JPOXMLDOC01-appb-C000004
     ［式中、Ｒ１は無置換又は置換基を有しても良いフェニル基、ピリミジン－２－イル基、２－ピリジル基、２－チエニル基、ピペリジノ基、シクロヘキシル基、アダマンチル基、トリフルオロメチル基、メトキシ基、フェノキシ基、４－フルオロフェノキシ基、アニリノ基を表し、Ｒ２は水素原子又はフッ素原子を表し、Ｒ３は炭素数１から６の直鎖状又は分岐状アルキル基を表す］
    Figure JPOXMLDOC01-appb-C000005
     　［式中、Ｒ４は無置換又は置換基を有しても良いフェニル基、炭素数５～７のシクロアルキル基、ピリジル基、チエニル基を表す］
    Figure JPOXMLDOC01-appb-C000006
     ［式中、Ｒ１は無置換又は置換基を有しても良いフェニル基、ピリミジン－２－イル基、２－ピリジル基、２－チエニル基、ピペリジノ基、シクロヘキシル基、アダマンチル基、トリフルオロメチル基、メトキシ基、フェノキシ基、４－フルオロフェノキシ基、アニリノ基を表し、Ｒ２は水素原子又はフッ素原子を表し、Ｒ３は炭素数１から６の直鎖状又は分岐状アルキル基を表し、Ｒ４は無置換又は置換基を有しても良いフェニル基、炭素数５～７のシクロアルキル基、ピリジル基、チエニル基を表す］     A method for producing a compound of the following general formula (I) by reacting a compound of the following general formula (II) with a compound of the following general formula (VIII).
    Figure JPOXMLDOC01-appb-C000004
     [Wherein R 1 is unsubstituted or optionally substituted phenyl, pyrimidin-2-yl, 2-pyridyl, 2-thienyl, piperidino, cyclohexyl, adamantyl, trifluoromethyl A methoxy group, a phenoxy group, a 4-fluorophenoxy group, an anilino group, R 2 represents a hydrogen atom or a fluorine atom, and R 3 represents a linear or branched alkyl group having 1 to 6 carbon atoms]
    Figure JPOXMLDOC01-appb-C000005
     [Wherein R 4 represents an unsubstituted or optionally substituted phenyl group, a cycloalkyl group having 5 to 7 carbon atoms, a pyridyl group, or a thienyl group]
    Figure JPOXMLDOC01-appb-C000006
     [Wherein R 1 is unsubstituted or optionally substituted phenyl, pyrimidin-2-yl, 2-pyridyl, 2-thienyl, piperidino, cyclohexyl, adamantyl, trifluoromethyl A methoxy group, a phenoxy group, a 4-fluorophenoxy group, an anilino group, R 2 represents a hydrogen atom or a fluorine atom, R 3 represents a linear or branched alkyl group having 1 to 6 carbon atoms, R 4 represents an unsubstituted or optionally substituted phenyl group, a cycloalkyl group having 5 to 7 carbon atoms, a pyridyl group, or a thienyl group.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116375648A (en) * 2023-03-22 2023-07-04 苏州农平科技发展有限公司 Preparation method of Bei Luosi intermediate

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000075103A1 (en) * 1999-06-09 2000-12-14 Kyorin Pharmaceutical Co., Ltd. SUBSTITUTED PHENYLPROPIONIC ACID DERIVATIVES AS AGONISTS TO HUMAN PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR) $g(a)
WO2001025181A1 (en) * 1999-10-01 2001-04-12 Eisai Co., Ltd. Carboxylic acid derivatives and drugs containing the same
WO2001092201A1 (en) * 2000-05-29 2001-12-06 Kyorin Pharmaceutical Co., Ltd. Substituted phenylpropionic acid derivatives
WO2002044131A1 (en) * 2000-11-29 2002-06-06 Kyorin Pharmaceutical Co., Ltd. Substituted carboxylic acid derivatives
JP2010539199A (en) * 2007-09-21 2010-12-16 サノフィ−アベンティス (Carboxylalkylene-phenyl) -phenyl-oxalamide, process for its preparation and its use as a medicament

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000075103A1 (en) * 1999-06-09 2000-12-14 Kyorin Pharmaceutical Co., Ltd. SUBSTITUTED PHENYLPROPIONIC ACID DERIVATIVES AS AGONISTS TO HUMAN PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR) $g(a)
WO2001025181A1 (en) * 1999-10-01 2001-04-12 Eisai Co., Ltd. Carboxylic acid derivatives and drugs containing the same
WO2001092201A1 (en) * 2000-05-29 2001-12-06 Kyorin Pharmaceutical Co., Ltd. Substituted phenylpropionic acid derivatives
WO2002044131A1 (en) * 2000-11-29 2002-06-06 Kyorin Pharmaceutical Co., Ltd. Substituted carboxylic acid derivatives
JP2010539199A (en) * 2007-09-21 2010-12-16 サノフィ−アベンティス (Carboxylalkylene-phenyl) -phenyl-oxalamide, process for its preparation and its use as a medicament

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE REGISTRY 31 August 2009 (2009-08-31), accession no. 178447-63-6 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116375648A (en) * 2023-03-22 2023-07-04 苏州农平科技发展有限公司 Preparation method of Bei Luosi intermediate

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