WO2017082377A1 - Dérivé pyrazolopyridine et utilisation de ce dernier - Google Patents

Dérivé pyrazolopyridine et utilisation de ce dernier Download PDF

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WO2017082377A1
WO2017082377A1 PCT/JP2016/083471 JP2016083471W WO2017082377A1 WO 2017082377 A1 WO2017082377 A1 WO 2017082377A1 JP 2016083471 W JP2016083471 W JP 2016083471W WO 2017082377 A1 WO2017082377 A1 WO 2017082377A1
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group
pyrazolo
isopropyl
pyridine
carboxylic acid
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PCT/JP2016/083471
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English (en)
Japanese (ja)
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土井　健史
敬祐 橘
直之 小林
智博 杠
憲司 石本
宮地　弘幸
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国立大学法人大阪大学
国立大学法人岡山大学
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Publication of WO2017082377A1 publication Critical patent/WO2017082377A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a pharmaceutical, a method for treating and / or preventing a disease, etc., containing a compound that selectively activates a peroxisome proliferator-responsive receptor (PPAR ⁇ ), and a novel compound that selectively activates PPAR ⁇ . .
  • PPAR ⁇ peroxisome proliferator-responsive receptor
  • LDL-C low density lipoprotein cholesterol
  • TG triglyceride
  • HDL-C high density lipoprotein cholesterol
  • 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 response element 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 a PPAR responsive element and activates transcription of various genes.
  • RXR retinoid X receptor
  • 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.
  • activation cofactors such as DRIP-205 and SRC-1
  • three types of subtypes ⁇ type, ⁇ / ⁇ type, ⁇ type
  • PPAR ⁇ is distributed in the liver, kidney, heart, muscle and the like having high fatty acid catabolism, and high expression is particularly observed in the liver.
  • PPAR ⁇ When transcription of a target gene is induced by PPAR ⁇ , a decrease in blood neutral fat, an increase in HDL cholesterol, a decrease in body weight, promotion of angiogenesis, etc. are induced (Non-patent Document 1).
  • Non-patent document 2 Of inflammatory diseases (Non-patent document 2), cancer (Non-patent document 3), skin diseases (inflammation of the skin, reduced barrier function, etc.) that have been reported to be related to PPAR ⁇ .
  • Non-patent Document 4 search for compounds that activate PPAR ⁇ has been vigorously conducted.
  • Fibrates that have been widely used as therapeutic agents for dyslipidemia so far are gene products that activate PPAR ⁇ and control fatty acid metabolism and intracellular transport (for example, acyl-CoA synthase, fatty acid-binding protein and lipoprotein lipase). ) And apolipoprotein gene products related to cholesterol and neutral lipid metabolism are positively or negatively controlled. As a result, administration of fibrate drugs reduces the synthesis of TG and very low density lipoprotein (VLDL) in the body, and increases lipoprotein lipase (LPL) activity in the vascular endothelium, thus promoting fat degradation. Is done.
  • VLDL very low density lipoprotein
  • LPL lipoprotein lipase
  • Non-patent Document 5 Known fibrates include fenofibrate (Ripantole (registered trademark)), bezafibrate (bezatol SR (registered trademark), bezalip (registered trademark)), gemfibrozil (ropid (registered trademark)) and the like (Non-patent Document 5).
  • these fibrate drugs are accompanied by side effects, particularly hepatic dysfunction (Non-patent Document 6), and therefore sufficient attention is required for their use.
  • PPAR ⁇ agonists play an important role in improving various phenomena associated with dyslipidemia, and they do not exhibit a wide range of effects as conventional fibrate drugs, and are more selective for PPAR ⁇ .
  • the development of therapeutic drugs that act is important. In recent years, compounds that selectively activate PPAR ⁇ have been reported, and their effects as therapeutic agents are expected (Patent Documents 1 to 4).
  • an object of the present invention is to provide a transcription activator that selectively activates PPAR ⁇ , a medicament containing the PPAR ⁇ transcription activator, and a method for treating and / or preventing diseases such as dyslipidemia.
  • an object of the present invention is to provide a novel compound (a novel selective PPAR ⁇ agonist) that selectively activates PPAR ⁇ .
  • the present invention is a 1H-pyrazolo [3,4-b] pyridine derivative represented by the following general formula (1), a salt thereof, a solvate thereof, or a hydrate thereof.
  • R 1 represents a hydrogen atom, a halogen atom, a linear or branched alkyl group having 1 to 10 carbon atoms, a linear or branched alkyl halide group having 1 to 10 carbon atoms, or 1 to 10 carbon atoms.
  • R 2 has 1 to 10 carbon atoms Linear or branched alkyl group or cyclic alkyl group
  • R 3 is a linear or branched alkyl group having 1 to 10 carbon atoms, fluoromethyl group, phenyl group or 2-thienyl group
  • R 4 is a carboxy group, ethoxy group
  • X represents a carbon atom or a nitrogen atom.
  • X is carbon, R 4 is 4-carboxy group, R 1 is 4-fluorine, R 2 is isopropyl group and R 3 is methyl group or cyclopropyl group, X is carbon, R 4 is 4-carboxy group, R 1 is 4-fluorine, R 2 is a cyclopropyl group and R 3 is an isopropyl group or cyclopropyl group, X is carbon, R 4 is a 4-carboxy group, R 1 is 4-fluorine, R 2 is a methyl group and R 3 Is a cyclopropyl group, and X is carbon, R 4 is a 4-carboxy group, R 1 is hydrogen, and R 2 and R 3 are methyl groups. ]
  • the present invention includes a 1H-pyrazolo [3,4-b] pyridine derivative represented by the following general formula (1), a salt thereof, a solvate thereof, or a hydrate thereof as an active ingredient.
  • PPAR ⁇ transcription activator a hydrogen atom, a halogen atom, a linear or branched alkyl group having 1 to 10 carbon atoms, a linear or branched alkyl halide group having 1 to 10 carbon atoms, or 1 to 10 carbon atoms.
  • R 2 has 1 to 10 carbon atoms Linear or branched alkyl group or cyclic alkyl group
  • R 3 is a linear or branched alkyl group having 1 to 10 carbon atoms, fluoromethyl group, phenyl group or 2-thienyl group
  • R 4 is a carboxy group, ethoxy group
  • X represents a carbon atom or a nitrogen atom]
  • the present invention also provides a pharmaceutical (therapeutic or therapeutic) comprising 1H-pyrazolo [3,4-b] pyridine derivative represented by the above general formula (1) or a salt thereof, or a solvate or hydrate thereof as an active ingredient.
  • a pharmaceutical therapeutic or therapeutic
  • Prophylactic agent or pharmaceutical composition, or a pharmaceutical (therapeutic or prophylactic agent) or pharmaceutical composition containing the PPAR ⁇ transcription activator.
  • the 1H-pyrazolo [3,4-b] pyridine derivative according to the present invention can selectively activate PPAR ⁇ . Therefore, the PPAR ⁇ transcription activator or medicament containing the 1H-pyrazolo [3,4-b] pyridine derivative according to the present invention is, for example, dyslipidemia, diabetes, obesity, hypertension, arteriosclerosis, liver disease. (Such as fatty liver diseases such as alcoholic or non-alcoholic steatohepatitis), diseases associated with metabolic syndrome such as angina pectoris, myocardial infarction, inflammatory diseases, cancer, skin diseases (such as skin inflammation and reduced barrier function) ) Can be used for prevention or treatment.
  • the present invention provides a novel 1H-pyrazolo [3,4-b] pyridine derivative that selectively activates PPAR ⁇ .
  • All other groups are dyslipidemia models given 10 w / v% fructose water, Control is 0.5 w / v% MC solution as negative control, Fenofibrate is fenofibrate 0.5 w / v% as positive control The result of administering a suspension suspended in MC solution is shown. Pre-treatment is a measurement value before treatment with a compound, and Post-treatment is a measurement value after treatment with a compound. It is the result of having investigated about the influence which the compound concerning this invention (compound of Example 20) has on blood parameters (HDL-C, LDL-C, AST, ALT, UN, and CK) using the dyslipidemia model rat. . Normal and Control are the same as described in FIG.
  • the first embodiment of the present invention is a 1H-pyrazolo [3,4-b] pyridine derivative represented by the above general formula (1), or a salt thereof, a solvate thereof, or a hydrate thereof. .
  • the second embodiment of the present invention provides a 1H-pyrazolo [3,4-b] pyridine derivative represented by the above general formula (1), a salt thereof, a solvate thereof, or a hydrate thereof.
  • Effective as a PPAR ⁇ transcription activator or a 1H-pyrazolo [3,4-b] pyridine derivative represented by the above general formula (1) or a salt thereof, or a solvate or hydrate thereof
  • R 1 is a hydrogen atom, a halogen atom, a linear or branched alkyl group having 1 to 10 carbon atoms, a linear or branched halogenated alkyl group having 1 to 10 carbon atoms, or a straight chain having 1 to 10 carbon atoms Or a branched alkoxy group, an unsubstituted or substituted phenyl group, an unsubstituted or substituted phenoxy group, an unsubstituted or substituted benzyloxy group, preferably a chlorine atom, a fluorine atom or a bromine atom It is.
  • the position of R 1 is preferably 4-position, 3-position or 2-position, more preferably 4-position or 3-position.
  • R 2 is a linear or branched alkyl group or cyclic alkyl group having 1 to 10 carbon atoms, preferably a methyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a 1- (ethyl) propyl group. More preferably, they are an isopropyl group and a cyclopropyl group.
  • R 3 is a linear or branched alkyl group having 1 to 10 carbon atoms, a fluoromethyl group, a phenyl group or a 2-thienyl group, preferably a methyl group, an ethyl group, a cyclopropyl group or an isopropyl group.
  • R 4 is a carboxy group, an ethoxycarbonyl group, or a propionic acid group having a substituent at the ⁇ -position, preferably a carboxy group, and particularly preferably a 4-carboxy group.
  • X is a carbon atom or a nitrogen atom, preferably a carbon atom.
  • the salt of the compound of the present invention represented by the general formula (1) may be a pharmaceutically acceptable salt.
  • an acidic group lithium, sodium, potassium, magnesium, calcium and the like Alkali metal and alkaline earth metal salts of ammonia, methylamine, dimethylamine, trimethylamine, dicyclohexylamine, tris (hydroxymethyl) aminomethane, N, N-bis (hydroxyethyl) piperazine, 2-amino-2-methyl-
  • Examples thereof include salts of amines such as 1-propanol, ethanolamine, N-methylglucamine and L-glucamine; and salts with basic amino acids such as lysine, ⁇ -hydroxylysine and arginine.
  • 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.
  • the 1H-pyrazolo [3,4-b] pyridine derivative represented by the general formula (1) includes stereoisomers such as tautomers and enantiomers unless otherwise specified. That is, when one or more asymmetric carbons are contained in the 1H-pyrazolo [3,4-b] pyridine derivative represented by the general formula (1), the stereochemistry of the asymmetric carbon is as follows: Each can independently take either the (R) form or the (S) form, and may exist as a stereoisomer such as an enantiomer or diastereoisomer of the derivative.
  • the active ingredient of the PPAR ⁇ transcription activator, medicament or pharmaceutical composition of the present invention any stereoisomer in a pure form, any mixture of stereoisomers, racemate and the like can be used.
  • the 1H-pyrazolo [3,4-b] pyridine derivative represented by the general formula (1) is not limited, and examples thereof include the following.
  • a transcriptional activator of PPAR ⁇ comprising a novel 1H-pyrazolo [3,4-b] pyridine derivative represented by the general formula (1) (activating (or inducing) transcription of a PPAR ⁇ target gene) Drug).
  • the transcriptional activator of PPAR ⁇ according to the present invention can be used for treatment and / or prevention of a disease caused by a decrease in PPAR ⁇ transcriptional activity.
  • a medicament (therapeutic or prophylactic agent) or medicament comprising as an active ingredient the 1H-pyrazolo [3,4-b] pyridine derivative represented by the general formula (1) or a salt thereof, or a solvate or hydrate thereof
  • a composition, or a pharmaceutical (therapeutic or prophylactic agent) or pharmaceutical composition containing the PPAR ⁇ transcription activator is also an embodiment of the present invention.
  • the medicament or pharmaceutical composition according to the present invention includes, for example, dyslipidemia, diabetes, obesity, hypertension, arteriosclerosis, liver diseases (such as fatty liver diseases such as alcoholic or non-alcoholic steatohepatitis), narrow It can be used for prevention and / or treatment of diseases associated with metabolic syndrome such as heart disease and myocardial infarction, inflammatory diseases, cancer, skin diseases (such as skin inflammation and reduced barrier function).
  • liver diseases such as fatty liver diseases such as alcoholic or non-alcoholic steatohepatitis
  • diseases associated with metabolic syndrome such as heart disease and myocardial infarction
  • inflammatory diseases such as cancer
  • skin diseases such as skin inflammation and reduced barrier function
  • the PPAR ⁇ transcription activator and medicament according to the present invention are active ingredients such as 1H-pyrazolo [3,4-b] pyridine derivative represented by the general formula (1) or a salt thereof, or a solvate or water thereof.
  • active ingredients such as 1H-pyrazolo [3,4-b] pyridine derivative represented by the general formula (1) or a salt thereof, or a solvate or water thereof.
  • the Japanese product itself may be administered, it is generally desirable to administer it in the form of a pharmaceutical composition containing these substances as active ingredients and one or more pharmaceutical additives.
  • the pharmaceutical composition may contain known ingredients that are effective in treating diseases associated with metabolic syndrome.
  • the kind of the medicine or pharmaceutical composition according to the present invention is not particularly limited, and dosage forms include tablets, capsules, granules, powders, syrups, suspensions, suppositories, ointments, creams, gels, Examples include patches, inhalants, injections and the like.
  • These preparations are prepared according to a conventional method.
  • the liquid preparation may be dissolved or suspended in water or other appropriate solvent at the time of use. Tablets and granules may be coated by a known method.
  • 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. Also good.
  • the preparation for oral administration or parenteral administration is provided in an arbitrary preparation form.
  • the dosage form include granules, fine granules, powders, hard capsules, soft capsules, syrups, emulsions, suspensions, liquids and the like for oral administration or pharmaceutical composition, intravenous administration.
  • Pharmaceuticals or pharmaceutical compositions for parenteral administration in the form of injections, drops, transdermal absorption agents, transmucosal absorption agents, nasal drops, inhalants, suppositories, etc. Can be prepared as a product.
  • 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.
  • the type of pharmaceutical additive used for the production of the pharmaceutical or pharmaceutical composition according to the present invention, the ratio of the pharmaceutical additive to the active ingredient, or the method for producing the pharmaceutical or pharmaceutical composition depends on the form thereof. Can be appropriately selected.
  • an additive for formulation an inorganic or organic substance, or a solid or liquid substance can be used, and it can generally be blended in an amount of 1 to 90% by weight based on the weight of the active ingredient. .
  • pharmaceutical additives include lactose, glucose, mannitol, dextrin, cyclodextrin, starch, sucrose, magnesium aluminate metasilicate, synthetic aluminum silicate, sodium carboxymethylcellulose, hydroxypropyl starch, carboxymethylcellulose calcium , Ion exchange resin, 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, polyso Bate, macrogol, vegetable oils, waxes, liquid paraffin, white petrolatum, fluorocarbons, nonionic surfactants, propylene glycol
  • 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 or polyvinylpyrrolidone, a disintegrant such as carboxymethylcellulose or 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 and talc.
  • granules or tablets should 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 with ethylcellulose, carnauba wax, hardened oil, etc. to make a sustained preparation. You can also.
  • an enteric solvent base such as hydroxypropylmethylcellulose phthalate or methacrylic acid-methyl methacrylate polymer
  • enteric solvent preparation or with ethylcellulose, carnauba wax, hardened oil, etc. to make a sustained preparation. You can also.
  • a hard capsule is filled with a powder or granule, or an active ingredient is directly or dissolved in glycerin, polyethylene glycol, sesame oil, olive oil, etc. 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. .
  • reticin, polysorbate 80, polyoxyethylene hydrogenated castor oil, etc. may 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 or pharmaceutical composition according to the present invention are not particularly limited, and may vary depending on 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. Accordingly, it is possible to make an appropriate selection based on the judgment of the doctor.
  • the daily dose for adults is about 0.01 to 1000 mg (active ingredient weight), 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 or pharmaceutical composition according to 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. it can.
  • a carrier that can prevent immediate removal from the body.
  • Such carriers can be biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Such materials can be readily prepared by those skilled in the art.
  • Liposome suspensions can also be used as pharmaceutically acceptable carriers.
  • Liposomes are prepared as a lipid composition comprising, but not limited to, phosphatidylcholine, cholesterol and PEG-derived phosphatidylethanol (PEG-PE) through a suitable pore size filter to obtain a suitable size for use in the reverse phase evaporation method. Can be purified by.
  • PEG-PE PEG-derived phosphatidylethanol
  • the medicament or pharmaceutical composition according to the present invention may be provided in the form of a kit together with instructions such as an administration method.
  • the drug contained in the kit is a container made of a material that maintains the activity of the components of the medicine or the pharmaceutical composition effectively for a long period of time, does not adsorb inside the container, and does not alter the components.
  • a sealed glass ampoule may include a buffer sealed in the presence of a neutral and non-reactive gas such as nitrogen gas.
  • instructions for use may be attached to the kit. Instructions for using the kit may be printed on paper or the like, stored on an electromagnetically readable medium such as a CD-ROM or DVD-ROM, and supplied to the user.
  • a PPAR ⁇ transcription activator or a medicine containing the same is administered to a patient or the like, for example, dyslipidemia, diabetes, obesity, hypertension, arteriosclerosis, liver disease
  • a method for preventing or treating diseases associated with metabolic syndrome such as angina pectoris and myocardial infarction, inflammatory diseases, cancer, skin diseases (such as skin inflammation and reduced barrier function).
  • treatment means to prevent or alleviate the progression and worsening of the disease state in a mammal suffering from a disease, etc., and thereby to prevent or alleviate the progression and worsening of the disease. It is treatment to do.
  • prevention means to prevent the onset or illness of the disease in advance for a mammal that may be affected by the disease, thereby preventing the onset of various symptoms of the disease in advance. It is treatment for the purpose.
  • 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.
  • R 1 is a hydrogen atom, a halogen atom, a linear or branched halogenated alkyl group having 1 to 10 carbon atoms, or a linear or branched group having 1 to 10 carbon atoms.
  • alkyl group a linear or branched alkoxy group having 1 to 10 carbon atoms, an unsubstituted or substituted phenyl group, an unsubstituted or substituted phenoxy group, an unsubstituted or substituted benzyloxy group
  • R 2 is a linear or branched alkyl group or cyclic alkyl group having 1 to 10 carbon atoms
  • R 3 is a linear or branched alkyl group having 1 to 10 carbon atoms, a fluoromethyl group, a phenyl group, or 2-thienyl.
  • R 1 represents a hydrogen atom, a halogen atom, a linear or branched alkyl group having 1 to 10 carbon atoms, a linear or branched alkyl halide group having 1 to 10 carbon atoms, or 1 to 10 carbon atoms.
  • the compound represented by: [Wherein, R 1 and X are as defined above.
  • the compound (B) represented by formula (B) is reacted (first step), and the following: [Wherein, R 1 , R 2 and X are as defined above. And the following compound (C): [Wherein R 3 has the same meaning as described above.
  • the compound (D) represented by the above is reacted (second step), and the following: [Wherein, R 1 , R 2 , R 3 and X are as defined above. ] It can manufacture by hydrolyzing the compound (E) represented by (3rd process).
  • the reaction in the first step can be carried out in hydrochloric acid, acetic acid, toluene, xylene and a mixed solvent of hydrochloric acid and ethanol or hydrochloric acid and propanol.
  • the reaction can be carried out at 100 to 200 ° C., preferably at the boiling temperature of the solvent.
  • the reaction time is usually 1 to 48 hours, preferably 12 to 24 hours.
  • the reaction in the second step can be carried out in hydrochloric acid, acetic acid, toluene, xylene and a mixed solvent of hydrochloric acid and ethanol or hydrochloric acid and propanol.
  • the reaction can be carried out at 100 to 200 ° C., preferably at the boiling temperature of the solvent.
  • the reaction time is usually 1 to 48 hours, preferably 12 to 24 hours.
  • the reaction in the third step can be performed under alkaline conditions.
  • the alkaline conditions can be carried out in a mixed solvent of lithium hydroxide, sodium hydroxide, potassium hydroxide and ethanol or propanol.
  • the reaction temperature can be 0 to 150 ° C., preferably room temperature to the reflux temperature of the solvent.
  • the reaction time is usually 1 to 48 hours, preferably 4 to 24 hours.
  • R 1 is a hydrogen atom, a halogen atom, a linear or branched alkyl group having 1 to 10 carbon atoms, or a linear chain having 1 to 10 carbon atoms.
  • R 2 is a linear or branched alkyl group or cyclic alkyl group having 1 to 10 carbon atoms
  • R 3 is a linear or branched alkyl group having 1 to 10 carbon atoms, fluoromethyl group, phenyl Group or 2-thienyl group
  • R 5 is a propionic acid group having a linear or branched alkyl group having 1 to 10 carbon atoms at the ⁇ -position
  • 1H-pyrazolo [3,4-b] wherein X is carbon Pi Derivative Compound (1b) can be produced by the following method (Scheme 2).
  • R 1 is a hydrogen atom, a halogen atom, a linear or branched alkyl group having 1 to 10 carbon atoms, a linear or branched alkyl halide group having 1 to 10 carbon atoms, or 1 to 10 carbon atoms.
  • R 3 is a linear or branched alkyl group having 1 to 10 carbon atoms, fluoromethyl group, phenyl group or 2-thienyl group
  • R 5 is carbon at the ⁇ -position
  • a propionic acid group having a linear or branched alkyl group of formula 1 to 10 is represented.
  • the compound (I) represented by formula (I) is reduced (seventh step), and the following: [Wherein, R 1 , R 2 , R 3 and R 5 have the same meanings as described above. ] It can manufacture by hydrolyzing the compound (J) represented by (8th process).
  • the reaction in the fourth step can be performed in diethyl ether, tetrahydrofuran, toluene, xylene using lithium aluminum hydride, diisobutylaluminum hydride, or borane-tetrahydrofuran complex as a reducing agent.
  • the reaction can be carried out at -70 ° C to 200 ° C, preferably 0 ° C to the boiling temperature of the solvent.
  • the reaction time is usually 1 to 48 hours, preferably 12 to 24 hours.
  • the reaction in the fifth step can be carried out in dichloromethane, chloroform, tetrahydrofuran or toluene using an oxidizing agent such as pyridinium chlorochromate, pyridinium dichromate or manganese dioxide as the oxidizing agent.
  • the reaction temperature can be 0 to 200 ° C., preferably from room temperature to the boiling temperature of the solvent.
  • the reaction time is usually 1 to 48 hours, preferably 12 to 24 hours.
  • the reaction in the sixth step is carried out in a solvent such as tetrahydrofuran, toluene, dioxane, N, N-dimethylformamide, as a base, for example, an alkali metal hydride such as sodium hydride, an organometallic compound such as butyl lithium, lithium diisopropylamide And metal alkoxides such as sodium methoxide and potassium t-butoxide can be used.
  • the reaction temperature can be ⁇ 20 ° C. to 150 ° C., preferably 0 ° C. to 50 ° C.
  • the reaction time is usually 1 to 48 hours, preferably 2 to 24 hours.
  • the reaction in the seventh step is carried out in the presence of a metal catalyst such as palladium-supported activated carbon, platinum-supported activated carbon, platinum oxide, rhodium-supported alumina, etc. in a solvent such as ethanol, methanol, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide and the like under a hydrogen pressure of 1 kgf. / Cm 2 to 5 kgf / cm 2 .
  • the reaction temperature can be 0 to 100 ° C., preferably room temperature to 80 ° C.
  • the reaction time is usually 1 to 48 hours, preferably 6 to 24 hours.
  • the reaction in the eighth step can be performed under alkaline conditions.
  • alkaline conditions lithium hydroxide, sodium hydroxide, potassium hydroxide or the like is used.
  • the reaction temperature can be 0 to 80 ° C., preferably room temperature to 60 ° C.
  • the reaction time is usually 1 to 48 hours, preferably 2 to 24 hours.
  • reaction solution was poured into 100 mL of 1 mol / L / sodium hydroxide aqueous solution and extracted with ethyl acetate (3 ⁇ 20 mL). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (n-hexane / AcOEt 4: 1 v / v) to obtain 0.90 g of the target compound as a yellow powder in a yield of 62%.
  • Example compounds shown in Tables 1 to 5 were synthesized in the same manner as in Example 1 for the compounds of the following general formula (1c) (Note that the PPAR-HM numbers are numbers used for data reduction). .
  • Example 51 Sodium 1- (4-chlorophenyl) -3-isopropyl-6-methyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylate (sodium salt of the compound of Example 1)
  • 1- (4-chlorophenyl) -3-isopropyl-6-methyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (0. 60 g, 1.82 mmol) 20 mL of a 1 mol / L aqueous sodium hydroxide solution was added, and the mixture was stirred with ice cooling for 10 minutes.
  • Example compound (1 ⁇ M) or fenofibrate (10 ⁇ M) was added to 10% charcoal / dextran treated FBS-DMEM, and further cultivated for 24 hours, followed by luciferase assay.
  • Dual-Luciferase (registered trademark) Reporter Assay System (Promega) reagent was used for the assay, and luciferase activity was measured using a luminometer according to the instructions attached to the kit. The measurement results are shown in Tables 6 to 9.
  • the compounds of Examples 42, 43, 44, 52 and 53 were purchased from Vitas-M, and the compound of Example 54 was purchased from Enamine.
  • the compounds according to the present invention have transcription activation activity (agonist activity) against PPAR ⁇ .
  • the strength of the transcriptional activation effect of these compounds is a known PPAR ⁇ agonist measured by the same method, which is equal to or higher than that of fenofibrate, a therapeutic agent clinically used as a therapeutic agent for dyslipidemia. Is a good PPAR ⁇ agonist.
  • the PPAR selectivity of the compound according to the present invention was examined by taking the compound of Example 1 as an example, and as shown in FIG. 1, it is clear that it has a selective transcription activation activity (agonist activity) for PPAR ⁇ . Became.
  • cDNA was synthesized according to the instructions attached to the SuperScriptIII TM RT (Life Technologies) kit. Using 25 ng of the synthesized cDNA, real time PCR was performed according to the instructions attached to QuantiTect (registered trademark) SYBR (registered trademark) Green PCR kit (QIAGEN) to analyze gene expression.
  • QuantiTect registered trademark
  • SYBR registered trademark
  • Green PCR kit QIAGEN
  • TBP was used for correction.
  • PDK4 102 bp fw; TTCCAGACCAACCAATTCACA (SEQ ID NO: 1) rv; CCTGGTGTTCAACTGTTGCC (SEQ ID NO: 2) PPAR ⁇ : 121 bp fw; CTATCATTTGCTGTGGAGATCG (SEQ ID NO: 3) rv; AAGATATCGTCCGGGTGGTT (SEQ ID NO: 4)
  • TBP 172 bp fw; AGCCAAGAGTGAAGAACAGTCC (SEQ ID NO: 5) rv; AAATTGTTGGTGGGTGAGCA (SEQ ID NO: 6) As shown in FIG.
  • the compounds according to the present invention increased the mRNA expression level of the PPAR ⁇ target gene (PDK4).
  • the compound of this invention is a PPAR (alpha) agonist also in a gene expression level.
  • test compound (the compound of Example 20) (0, 1, 3 and 10 mg / kg) suspended in a 0.5 w / v% methylcellulose solution and a fenofibrate as a control compound in a 6-week-old dyslipidemia model rat (30 mg / kg) was orally administered once a day for 14 consecutive days.
  • 10 w / v% fructose water was freely ingested.
  • blood was collected from the abdominal aorta under anesthesia, allowed to stand at room temperature for 20-60 minutes, and then serum was obtained by centrifugation.
  • Serum triglyceride level (GPO / HMMPS method, glycerol elimination method), aspartate transaminase level (corresponding to JSCC standardization), alanine transaminase level (corresponding to JSCC standardization), creatine kinase level (corresponding to JSCC standardization), urea nitrogen level (urease / GIDH method), HDL cholesterol level (selective elimination method), and LDL cholesterol level (selective elimination method) were measured using an automatic analyzer JCA-BM6070 (JEOL). As shown in FIG. 3, it was confirmed that the serum triglyceride (TG) level was increased by fructose loading.
  • JEOL automatic analyzer JCA-BM6070
  • the compound according to the present invention (the compound of Example 20) was administered at a dose of 3 mg / kg or more, an effect of decreasing the rat serum triglyceride value was observed.
  • the level of the lowering effect was similar to that of rat serum TG when fenofibrate was administered at 30 mg / kg.
  • the compound of the present invention has an action for improving dyslipidemia.
  • the compound of the present invention gives fluctuations to blood parameters of rats due to fructose load. That is, serum HDL-C (HDL cholesterol) tended to decrease by administration of the compound of the present invention, but the degree was less than that of fenofibrate. Neither the compound of the present invention (Example 20) nor fenofibrate affected AST (aspartate aminotransferase), ALT (alanine aminotransferase) and UN (urea nitrogen). On the other hand, administration of the compound of the present invention decreased CK (creatine kinase), and its action was similar to that of fenofibrate. Also in this respect, the compound of the present invention has an action for improving dyslipidemia.
  • AST aspartate aminotransferase
  • ALT alanine aminotransferase
  • UN urea nitrogen
  • Example 4 Measurement of lipid lowering action of the compound according to the present invention (the compound of Example 1 and the compound of Example 51)
  • Male Crl: CD (SD) rats (Nippon Charles River) were fed with solid feed (Oriental Yeast Industry).
  • a 7-week-old rat was allowed to freely consume 25 w / v% fructose water using a water bottle, and was bred for 3 weeks to be a dyslipidemia model rat.
  • An 11-week-old dyslipidemia model rat was mixed with the compound of Example 1 (10 mg / kg), the compound of Example 51 (10 mg / kg), and the control compound fenofibrate (30 mg / kg), pema Fibrate (1 mg / kg) was orally administered once a day for 14 consecutive days (3 mice per administration group).
  • the compound of Example 51 was suspended in water for injection, and the other compounds were suspended in a 0.5 w / v% methylcellulose solution.
  • 25 w / v% fructose water was freely ingested.
  • the animals were fasted for 5 hours before blood collection, and blood was collected from the abdominal aorta under anesthesia 4 hours after the final administration.
  • Serum triglyceride level (GPO / HMMPS method, glycerol elimination method), aspartate transaminase level (corresponding to JSCC standardization), alanine transaminase level (corresponding to JSCC standardization), creatine kinase level (corresponding to JSCC standardization), urea nitrogen level (urease / GIDH method), HDL cholesterol level (selective elimination method), and LDL cholesterol level (selective elimination method) were measured using an automatic analyzer JCA-BM6070 (JEOL).
  • the organ weight was measured by taking out the target organ and using an electronic balance (HR-200, A & D Co., Ltd.). Furthermore, the relative weight per 100 g was calculated from the body weight measured using an electronic balance (GX-4000, A & D Co., Ltd.).
  • the compound of Example 1 and the compound of Example 51 for the dyslipidemia model rat were compared with the known lipid abnormality-improving drugs Fenofibrate and Pemafibrate, and the blood triglyceride was comparable or higher. It was suggested that a value lowering effect was exhibited (FIG. 6). Regarding the effects on organs, the compound of Example 1 and the compound of Example 51 are less in comparison with the increase in liver weight observed with Fenofibrate and Pemafibrate, and the kidney weight observed with Fenofibrate Compared with the increase, the degree of the compound of Example 51 was low, suggesting that the compound of the present invention is highly safe (FIG. 5B).
  • the compound according to the present invention activates PPAR ⁇ transcription. Therefore, a medicament containing these compounds as an active ingredient is expected to exert an effect on the treatment or prevention of diseases such as dyslipidemia.

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Abstract

La présente invention concerne : un activateur transcriptionnel de PPARα comprenant comme principe actif un dérivé 1-H-pyrazolo[3,4-b]pyridine représenté par la formule générale (1) ou un sel de ce dernier, ou un solvate ou un hydrate de ce dernier ; et un nouveau composé pour activer PPARα de façon sélective. [Dans la formule, R1 représente un atome d'hydrogène, un atome d'halogène, un groupe alkyle en C1-10 linéaire ou ramifié, ou similaire, R2 représente un groupe alkyle en C1-10 linéaire ou ramifié ou un groupe alkyle cyclique, R3 représente un groupe alkyle en C1-10 linéaire ou ramifié, un groupe fluorométhyle, un groupe phényle ou un groupe 2-thiényle, R4 représente un groupe carboxy, un groupe éthoxycarbonyle ou un groupe acide propionique présentant un groupe alkyle en C1-10 linéaire ou ramifié en position α, et X représente un atome de carbone ou un atome d'azote].
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JP2019011325A (ja) * 2017-06-30 2019-01-24 興和株式会社 医薬組成物
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WO2022259993A1 (fr) * 2021-06-07 2022-12-15 国立大学法人大阪大学 ACTIVATEUR TRANSCRIPTIONNEL DE PPARα ET LEUR UTILISATION PHARMACEUTIQUE

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