WO2015046317A1 - Nouveau dérivé d'acétylène-amide - Google Patents

Nouveau dérivé d'acétylène-amide Download PDF

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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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pparγ
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thienyl
pyrimidin
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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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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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.

Abstract

La présente invention vise à fournir de nouveaux dérivés d'acétylène-amide, c'est-à-dire un composé ayant une activité antagoniste sur tous les PPARα, PPARβ/δ et PPARγ, un composé ayant une activité antagoniste sur au moins un sous-type parmi PPARα, PPARβ/δ et PPARγ, et un composé capable d'inhiber une activité antagoniste sélective de PPARγ. Un composé fourni par la présente invention est un dérivé d'acétylène-amide représenté par la formule générale (I).
PCT/JP2014/075403 2013-09-30 2014-09-25 Nouveau dérivé d'acétylène-amide WO2015046317A1 (fr)

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Citations (5)

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Publication number Priority date Publication date Assignee Title
WO2000075103A1 (fr) * 1999-06-09 2000-12-14 Kyorin Pharmaceutical Co., Ltd. DERIVES D'ACIDE PHENYLPROPIONIQUE SUBSTITUES COMME AGONISTES DU RECEPTEUR HUMAIN ACTIVE DE LA PROLIFERATION DES PEROXYSOMES (PPAR) $g(a)
WO2001025181A1 (fr) * 1999-10-01 2001-04-12 Eisai Co., Ltd. Derives d'acide carboxylique et medicaments les contenant
WO2001092201A1 (fr) * 2000-05-29 2001-12-06 Kyorin Pharmaceutical Co., Ltd. Derives substitues d'acide phenylpropionique
WO2002044131A1 (fr) * 2000-11-29 2002-06-06 Kyorin Pharmaceutical Co., Ltd. Dérivés d'acide carboxylique substitués
JP2010539199A (ja) * 2007-09-21 2010-12-16 サノフィ−アベンティス （カルボキシルアルキレン−フェニル）−フェニル−オキサルアミド、その製造方法、及び薬剤としてのその使用

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Publication number Priority date Publication date Assignee Title
WO2000075103A1 (fr) * 1999-06-09 2000-12-14 Kyorin Pharmaceutical Co., Ltd. DERIVES D'ACIDE PHENYLPROPIONIQUE SUBSTITUES COMME AGONISTES DU RECEPTEUR HUMAIN ACTIVE DE LA PROLIFERATION DES PEROXYSOMES (PPAR) $g(a)
WO2001025181A1 (fr) * 1999-10-01 2001-04-12 Eisai Co., Ltd. Derives d'acide carboxylique et medicaments les contenant
WO2001092201A1 (fr) * 2000-05-29 2001-12-06 Kyorin Pharmaceutical Co., Ltd. Derives substitues d'acide phenylpropionique
WO2002044131A1 (fr) * 2000-11-29 2002-06-06 Kyorin Pharmaceutical Co., Ltd. Dérivés d'acide carboxylique substitués
JP2010539199A (ja) * 2007-09-21 2010-12-16 サノフィ−アベンティス （カルボキシルアルキレン−フェニル）−フェニル−オキサルアミド、その製造方法、及び薬剤としてのその使用

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