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WO2015129845A1 - Nouveau dérivé de tétrahydro-pyrido-pyrimidinone - Google Patents

Nouveau dérivé de tétrahydro-pyrido-pyrimidinone Download PDF

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Publication number
WO2015129845A1
WO2015129845A1 PCT/JP2015/055768 JP2015055768W WO2015129845A1 WO 2015129845 A1 WO2015129845 A1 WO 2015129845A1 JP 2015055768 W JP2015055768 W JP 2015055768W WO 2015129845 A1 WO2015129845 A1 WO 2015129845A1
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Prior art keywords
group
phenyl
acceptable salt
pharmaceutically acceptable
pyrido
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English (en)
Japanese (ja)
Inventor
隆宏 小柴
昌嗣 野口
渉 宮永
大角　幸治
佳代 松本
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Ajinomoto Co Inc
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Ajinomoto Co Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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 novel tetrahydropyridopyrimidinone derivative having monoacylglycerol acyltransferase inhibitory activity, a physiologically acceptable salt thereof, and a pharmaceutical composition containing the same.
  • Numerous diseases such as impaired glucose tolerance, type 2 diabetes, abnormal lipid metabolism, and hypertension are known as health disorders caused by or related to obesity, and it is important to treat obesity for the purpose of preventing or improving these diseases. is there.
  • diet therapy, exercise therapy, and behavior therapy are performed, and drug therapy is introduced if necessary.
  • drugs such as orlistat, mazindol, sibutramine and the like are used as anti-obesity drugs, but there are no drugs that are sufficiently satisfactory in terms of both drug efficacy and side effects, and the development of better drugs is desired.
  • Dietary neutral fat (triacylglycerol (TG)) is hydrolyzed to 2-monoacylglycerol (MG) and free fatty acids by pancreatic lipase in the digestive tract, and then absorbed into the intestinal mucosal epithelial cells of the small intestine. Is re-synthesized.
  • This resynthesis reaction is known to be carried out by a monoacylglycerol pathway catalyzed by monoacylglycerol acyltransferase (MGAT) and diacylglycerol acyltransferase (DGAT) and a glycerol triphosphate pathway.
  • MGAT is an enzyme that acylates MG to diacylglycerol (DG), and three isoforms of MGAT1, MGAT2, and MGAT3 have been identified so far. Of these, it is speculated that MGAT2 and MGAT3, which are highly expressed in the small intestine, are involved in TG resynthesis in the small intestine. In experiments using mice, it has been reported that the expression of MGAT2 in the small intestine is increased and MGAT activity is increased by high-fat diet loading (Non-patent Document 1). In addition, in MGAT2 gene-deficient mice, suppression of weight gain due to high-fat diet loading, suppression of insulin resistance, suppression of blood cholesterol elevation, suppression of fatty liver formation, and increase in energy consumption were confirmed. And a key enzyme for energy metabolism (Non-patent Document 2). From these findings, it was predicted that MGAT2 enzyme activity inhibitors are useful for the treatment or prevention of obesity and various diseases related to obesity.
  • DG diacylglycerol
  • Patent Documents 1 to 4 So far, several compounds have been described in Patent Documents 1 to 4 as compounds having MGAT2 inhibitory activity. However, the MGAT2 inhibitory activity of these compounds is not so high, and the MGAT2 inhibitory activity is higher than that of conventional compounds. Therefore, there is a great demand for new compounds useful for the suppression of fat absorption and the treatment / prevention of obesity. .
  • the present invention has been made in view of the above problems, and an object thereof is to provide a novel compound having a high MGAT2 inhibitory activity.
  • the present inventors have found that a compound represented by the following general formula (I) or a physiologically acceptable salt thereof has an extremely high MGAT2 inhibitory action, and completed the present invention. That is, the present invention has the following configuration.
  • R 1 represents a linear C 1-6 alkylene group (optionally substituted with a deuterium atom);
  • R 2 represents a single bond, —S 1 —US 2 —V—, —S 3 —C ( ⁇ O) —NH—S 4 —, or —S 5 —WS 6 —;
  • S 1 and S 2 each independently represents a linear C 1-6 alkylene group, and optionally substituted with 1 to 3 identical or different substituents selected from C 1-3 alkyl groups.
  • S 3 represents a linear C 1-6 alkylene group, and if necessary, the same or different 1 to 3 selected from a deuterium atom, a halogen atom, a C 1-3 alkyl group, and a C 1-3 haloalkyl group Optionally substituted with 3 substituents;
  • S 4 represents a single bond, a C 1-6 alkylene group or —C 1-6 alkylene-O—;
  • S 5 represents a C 1-6 hydroxyalkyl group, a C 1-6 aminoalkyl group, and a C 1-6 thioalkyl group (if necessary, a hydroxyl group, an amino group, or a mercapto group contained in these groups is a C 1-
  • W represents a single bond, —S—, —O—, or —NH—;
  • S 6 represents a single bond or a C
  • Y represents a single bond, —S—, —O—, or —NR 5 — (wherein R 5 represents a hydrogen atom, a C 1-6 alkyl group, or a C 1-6 haloalkyl group);
  • Z represents a single bond or a C 1-6 alkylene group;
  • R 3 represents a C 3-8 alkyl group, a C 3-8 cycloalkyl group, or a 3- to 8-
  • R 1 is a linear C 1-3 alkylene group.
  • S 1 and S 2 each independently represent a linear C 1-3 alkylene group; U represents —O— or —NJ— (wherein J represents a hydrogen atom, a C 1-3 alkyl group, or a C 1-3 hydroxyalkyl group); V represents —O—; S 3 represents a linear C 1-3 alkylene group; S 4 represents a single bond or —C 1-3 alkylene-O—; S 5 represents a linear C 1-3 alkylene group substituted with 1 to 2 C 1-3 hydroxyalkyl groups; W represents a single bond or —O—; S 6 represents a single bond, ⁇ 1> or ⁇ 2> or a pharmaceutically acceptable salt thereof.
  • ⁇ 4> Q represents a C 3-8 cycloalkyl group, a phenyl group, a naphthyl group, an indanyl group, or a tetralinyl group, and optionally selected from a halogen atom, a C 1-3 alkyl group, and a C 1-3 haloalkyl group Or a pharmaceutically acceptable salt thereof according to any one of ⁇ 1> to ⁇ 3>, which may be substituted with the same or different 1 to 3 substituents.
  • ⁇ 5> The compound or a pharmaceutically acceptable salt thereof according to any one of the above ⁇ 1> to ⁇ 4>, wherein Y is —S—, —O—, or —NH—.
  • ⁇ 6> The compound according to any one of the above ⁇ 1> to ⁇ 5> or a pharmaceutically acceptable salt thereof, wherein Z is a single bond or a C 1-3 alkylene group.
  • ⁇ 7> The compound according to any one of the above ⁇ 1> to ⁇ 6> or a pharmaceutically acceptable salt thereof, wherein R 3 is a C 3-6 alkyl group or a C 3-7 cycloalkyl group.
  • R 4 is a C 1-6 alkyl group, a phenyl group, a C 3-7 cycloalkyl group, or a 5- or 6-membered saturated or unsaturated heterocyclic group. Or a pharmaceutically acceptable salt thereof.
  • a fat absorption inhibitor comprising the compound according to any one of the above ⁇ 1> to ⁇ 9> or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a prophylactic and / or therapeutic agent for obesity comprising as an active ingredient the compound according to any one of the above ⁇ 1> to ⁇ 9> or a pharmaceutically acceptable salt thereof.
  • a prophylactic and / or therapeutic agent for dyslipidemia comprising the compound according to any one of the above ⁇ 1> to ⁇ 9> or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a pharmaceutical composition comprising the compound according to any one of the above ⁇ 1> to ⁇ 9> or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof has an extremely high MGAT inhibitory activity as compared with conventional compounds. Therefore, it is excellent as an MGAT inhibitor and can be suitably used for suppression of fat absorption and treatment / prevention of obesity.
  • C 1-6 alkylene group is a divalent group derived by removing two hydrogen atoms at both ends of a linear aliphatic hydrocarbon having 1 to 6 carbon atoms. Specific examples include groups such as methylene, ethylene, and propylene.
  • the “C 1-6 alkyl group” is a monovalent group derived by removing one arbitrary hydrogen atom from a linear or branched aliphatic hydrocarbon having 1 to 6 carbon atoms.
  • C 3-8 cycloalkyl group is a monovalent group derived by removing one arbitrary hydrogen atom from a cyclic aliphatic hydrocarbon having 3 to 8 carbon atoms.
  • groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • haloalkyl group means a group (halogenated alkyl group) in which part or all of the hydrogen atoms constituting the alkyl group are replaced with halogen atoms.
  • haloalkoxy group means a group (halogenated alkoxy group) in which part or all of the hydrogen atoms constituting the alkoxy group are replaced with halogen atoms.
  • Hydroxyl group means a group in which part or all of the hydrogen atoms constituting the alkyl group are replaced with hydroxyl groups.
  • aminoalkyl group means a group in which part or all of the hydrogen atoms constituting the alkyl group are replaced with amino groups.
  • the “thioalkyl group” means a group in which part or all of the hydrogen atoms constituting the alkyl group are replaced with a mercapto group.
  • an “alkyl group”, an “alkylene group” and an “alkoxy group” (an alkyl group constituting a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, etc., (Also including an alkoxy group) may be linear or branched.
  • “Halogen atom” means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • Heterocyclic group means one hydrogen atom removed from a saturated or unsaturated ring (heterocycle) containing 1 to 3 heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom. Means group. Examples of the hetero atom include an oxygen atom, a nitrogen atom, and a sulfur atom.
  • the “bicyclic heterocyclic group” means a group obtained by removing one hydrogen atom from a condensed ring obtained by condensing two rings including a heterocyclic ring.
  • Examples of the saturated heterocyclic group include groups in which one hydrogen atom has been removed from piperidine, piperazine, pyrrolidine, tetrahydrofuran and the like.
  • Examples of the unsaturated heterocyclic group include groups in which one hydrogen atom has been removed from thiophene, furan, oxazole, thiazole, oxadiazole, pyridine and the like.
  • Examples of the unsaturated bicyclic heterocyclic group include groups in which one hydrogen atom has been removed from indole, indoline, benzothiophene, benzofuran, benzoxazole, benzodioxazole, and the like.
  • the number of substituents may be 1, 2 or 3 and the plurality of substituents may be the same or different.
  • R 1 represents a linear C 1-6 alkylene group (optionally substituted with a deuterium atom).
  • R 1 is more preferably a linear C 1-3 alkylene group, and even more preferably a linear C 1-2 alkylene group. That is, as R 1 , a methylene group or an ethylene group is particularly preferably used.
  • Q is a C 3-8 cycloalkyl group, a phenyl group, a naphthyl group, an indanyl group, a tetralinyl group, a 3-6 membered saturated or unsaturated heterocyclic group, or a 9-10 membered saturated group. Or represents an unsaturated bicyclic heterocyclic group.
  • Q is deuterium atom, halogen atom, hydroxyl group, amino group, C 1-3 alkyl group, C 1-3 haloalkyl group, C 1-3 alkylthio group, nitrile group, C 1-3 alkoxy group, C, if necessary.
  • Q is preferably a C 3-8 cycloalkyl group, a phenyl group, a naphthyl group, an indanyl group, or a tetralinyl group, more preferably a phenyl group, a naphthyl group, an indanyl group, or a tetralinyl group, and even more preferably a phenyl group or an indanyl group.
  • the substituent is preferably a halogen atom, a C 1-3 alkyl group, or a C 1-3 haloalkyl group, and more preferably a halogen atom or a C 1-3 haloalkyl group.
  • the number of the substituent is more preferably 1 to 3, and even more preferably 1 to 2. It is also preferred that the group of Q is unsubstituted.
  • Y represents a single bond, —S—, —O—, or —NR 5 — (wherein R 5 represents a hydrogen atom, a C 1-6 alkyl group, or a C 1-6 haloalkyl group. Represents).
  • Y is preferably —S—, —O— or —NH—, more preferably —S— or —NH—, and still more preferably —S—.
  • Z represents a single bond or a C 1-6 alkylene group.
  • Z is preferably a single bond or a C 1-3 alkylene group, more preferably a single bond or a C 1-2 alkylene group, still more preferably a single bond or a methylene group, and particularly preferably a single bond.
  • R 3 represents a C 3-8 alkyl group, a C 3-8 cycloalkyl group, or a 3- to 8-membered saturated or unsaturated heterocyclic group, and if necessary, a deuterium atom, It may have the same or different 1 to 7 substituents selected from a halogen atom, a C 1-3 alkyl group, a C 1-3 haloalkoxy group, and a C 1-3 haloalkyl group.
  • R 3 is preferably a C 3-6 alkyl group or a C 3-7 cycloalkyl group, more preferably a C 3-6 cycloalkyl group, still more preferably a C 4-5 cycloalkyl group, and particularly preferably a cyclobutyl group.
  • R 3 has a substituent, the number of the substituent is 1 to 7, preferably 1 to 6, more preferably 1 to 4, still more preferably 1 to 2, and particularly preferably 1 preferable. It is also preferred that the R 3 group is unsubstituted.
  • R 4 represents a C 1-6 alkyl group, a phenyl group, a C 3-8 cycloalkyl group, or a 3- to 8-membered saturated or unsaturated heterocyclic group, and if necessary, 1 to the same or different selected from deuterium atom, halogen atom, hydroxyl group, carboxyl group, C 1-3 alkyl group, C 1-3 haloalkyl group, C 1-3 alkoxy group, and C 1-3 haloalkoxy group It may have 7 substituents.
  • R 4 is more preferably a C 1-6 alkyl group, a phenyl group, a C 3-7 cycloalkyl group, or a 5- or 6-membered saturated or unsaturated heterocyclic group, and even more preferably a phenyl group.
  • the number of the substituent is 1 to 7, preferably 1 to 6, more preferably 1 to 4, still more preferably 1 to 2, and particularly preferably 1 preferable. It is also preferred that the R 4 group is unsubstituted.
  • R 2 is a single bond, —S 1 —US 2 —V—, —S 3 —C ( ⁇ O) —NH—S 4 —, or —S 5 —WS 6 represents-.
  • S 1 and S 2 each independently represents a linear C 1-6 alkylene group, and optionally substituted with 1 to 3 identical or different substituents selected from C 1-3 alkyl groups. Or two substituents on one carbon atom (methylene group) constituting the linear C 1-6 alkylene group may be bonded to form a 3- to 7-membered ring together with the carbon atom.
  • C3-C7 cycloalkylene preferably a 3- to 5-membered ring (C3-C5 cycloalkylene), more preferably a 3-membered ring (cyclopropylene) may be formed.
  • U and V each independently represent —S—, —O—, or —NJ— (wherein J represents a hydrogen atom, a C 1-6 alkyl group, or a C 1-6 hydroxyalkyl group).
  • S 3 represents a linear C 1-6 alkylene group, and if necessary, the same or different 1 to 3 selected from a deuterium atom, a halogen atom, a C 1-3 alkyl group, and a C 1-3 haloalkyl group It may be substituted with 3 substituents.
  • S 4 represents a single bond, a C 1-6 alkylene group or —C 1-6 alkylene-O—.
  • S 5 represents a C 1-6 hydroxyalkyl group, a C 1-6 aminoalkyl group, and a C 1-6 thioalkyl group (if necessary, a hydroxyl group, an amino group, or a mercapto group contained in these groups is a C 1- A linear C 1-6 alkylene group substituted with 1 to 3 substituents selected from (which may be substituted with 3 alkyl groups).
  • W represents a single bond, —S—, —O—, or —NH—.
  • S 6 represents a single bond or a C 1-3 alkylene group.
  • S 1 and S 2 are each independently preferably a linear C 1-3 alkylene group, and a linear C 1- Two alkylene groups are more preferred. That is, as S 1 and S 2 , a methylene group or an ethylene group is particularly preferably used independently.
  • U is preferably —O— or —NJ— (wherein J represents a hydrogen atom, a C 1-3 alkyl group, or a C 1-3 hydroxyalkyl group), and more preferably —O—.
  • V is preferably —O—.
  • the number of substituents for S 1 and / or S 2 is preferably 1 to 2, more preferably 1. It is also preferred that the S 1 and / or S 2 groups are unsubstituted.
  • S 3 is preferably a linear C 1-3 alkylene group, and a linear C 1-2 alkylene group Is more preferable. That is, as S 3 , a methylene group or an ethylene group is particularly preferably used.
  • S 3 has a substituent, the substituent is the same or different 1 to 2 substituents selected from a deuterium atom, a halogen atom, a C 1-3 alkyl group, and a C 1-3 haloalkyl group. It is preferably substituted and more preferably substituted with one substituent. It is also preferred that S 3 is unsubstituted.
  • S 4 is preferably a single bond or —C 1-3 alkylene-O—.
  • S 5 represents a C 1-3 hydroxyalkyl group, a C 1-3 aminoalkyl group, and a C 1-3 thioalkyl group (optionally these The hydroxyl group, amino group or mercapto group contained in the group may be substituted with 1 to 2, preferably 1 substituent selected from C 1-3 alkyl group).
  • a chain C 1-3 alkylene group is preferred.
  • S 5 is more preferably a linear C 1-3 alkylene group substituted with 1 to 2, preferably 1 C 1-3 hydroxyalkyl group.
  • W is preferably a single bond or —O—, more preferably —O—.
  • S 6 is preferably a single bond.
  • a compound selected from the group consisting of the following compounds is particularly preferable.
  • 2-Cyclobutylsulfanyl-6- [3- (indan-2-ylamino) propanoyl] -3-phenyl-7,8-dihydro-5H-pyrido [4,3-d] pyrimidin-4-one ⁇ )- 2-Cyclobutylsulfanyl-6- [3- (indan-1-ylamino) propanoyl] -3-phenyl-7,8-dihydro-5H-pyrido [4,3-d] pyrimidin-4-one
  • Examples of the pharmaceutically acceptable salt of the compound represented by the general formula (I) include acid addition salts, alkali metal salts, and alkaline earth metal salts.
  • the acid addition salt may be an organic acid salt or an inorganic acid salt.
  • Organic salts include trifluoroacetate, oxalate, maleate, fumarate, malonate, lactate, malate, citrate, tartrate, methanesulfonate, p-toluenesulfone Examples include acid salts.
  • Examples of the inorganic acid salt include hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate and the like.
  • Examples of the alkali metal salt include sodium salt and potassium salt.
  • alkaline earth metal salts include calcium salts and magnesium salts.
  • the salt as the organic base include salts with ammonia, methylamine, triethylamine, N-methylmorpholine and the like.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof includes hydrates and solvates.
  • Monoacylglycerol acyltransferase is an enzyme that acylates 2-monoacylglycerol (MG) to diacylglycerol (DG), which is then triacylglycerol (TGAT) by diacylglycerol acyltransferase (DGAT).
  • TG is accumulated in tissues such as liver and fat. Therefore, the compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof that can remarkably inhibit the activity of monoacylglycerol acyltransferase is the activity of monoacylglycerol acyltransferase (MGAT).
  • Is useful as a MGAT inhibitor particularly a monoacylglycerol acyltransferase 2 (MGAT2) inhibitor. Further, by inhibiting monoacylglycerol acyltransferase activity, resynthesis from MG to DG and TG is inhibited, and as a result, fat absorption into the body, particularly into the liver and adipose tissue is suppressed. Therefore, the compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof is useful as a fat absorption inhibitor.
  • MGAT2 monoacylglycerol acyltransferase 2
  • the compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof that inhibits MGAT activity is used as a therapeutic and / or prophylactic agent for dyslipidemia, or a therapeutic agent for obesity and It is useful as a preventive agent.
  • the compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof is used as a pharmaceutical composition, particularly a pharmaceutical composition for treating and / or preventing dyslipidemia, or It is useful as a pharmaceutical composition for treating and / or preventing obesity.
  • dyslipidemia include hypercholesterolemia and hypertriglyceridemia.
  • the MGAT inhibitor, fat absorption inhibitor, therapeutic agent and / or prophylactic agent for dyslipidemia of the present invention, therapeutic agent and / or prophylactic agent for obesity, and pharmaceutical composition are compounds represented by general formula (I)
  • a pharmaceutically acceptable salt thereof may be used alone, or may be used in the form of a composition containing the compound represented by formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient. .
  • the composition may contain, for example, a carrier (preferably a pharmaceutically or physiologically acceptable solid or liquid carrier) or an additive.
  • a stabilizer, a wetting agent, an emulsifier, a binder, an isotonic agent and the like can be appropriately added as necessary.
  • the carrier include glucose, lactose, sucrose, starch, mannitol, dextrin, fatty acid glyceride, polyethylene glycol, hydroxyethyl starch, ethylene glycol, polyoxyethylene sorbitan fatty acid ester, gelatin, albumin, amino acid, water, and physiological saline. Water etc. are mentioned.
  • the additive is not particularly limited as long as it is usually used for the purpose depending on the purpose. Specifically, for example, flavoring, sugar, sweetener, dietary fiber, vitamins, sodium glutamate Amino acids such as (MSG), nucleic acids such as inosine monophosphate (IMP), inorganic salts such as sodium chloride, and water.
  • MSG sodium glutamate Amino acids
  • IMP inosine monophosphate
  • inorganic salts such as sodium chloride, and water.
  • the MGAT inhibitor, fat absorption inhibitor, dyslipidemia treatment and / or prevention agent, obesity treatment and / or prevention agent, and pharmaceutical composition of the present invention are not limited to physical properties such as dry powder, paste, and solution. It can be used in an orally administrable form. Examples of such orally administrable forms include tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets), capsules (including soft capsules and microcapsules), granules, powders, and troches. Agents, syrups, emulsions, suspensions, films (eg, orally disintegrating films), lyophilizers and the like.
  • the MGAT inhibitor, fat absorption inhibitor, lipid metabolism disorder treatment and / or prevention agent, obesity treatment and / or prevention agent, and pharmaceutical composition of the present invention include an injection (eg, subcutaneous injection, intravenous injection). Internal injection, intramuscular injection, intraperitoneal injection, infusion), external preparation (eg, transdermal preparation, ointment), suppository (eg, rectal suppository, vaginal suppository), pellet, nasal preparation Also, it can be used in the form of parenteral agents such as pulmonary agents (inhalants) and eye drops.
  • These can be safely administered orally or parenterally (eg, topical, rectal, intravenous administration).
  • These preparations may be controlled-release preparations (eg, sustained-release microcapsules) such as immediate-release preparations or sustained-release preparations.
  • These preparations can be prepared by conventional means on the preparation. Furthermore, you may use in the form which accommodated the compound represented by the said general formula (I), or its pharmacologically acceptable salt in the granule, tablet, gelatin capsule, etc. which are used with a supplement.
  • the dose of the compound represented by (I) or a pharmaceutically acceptable salt thereof may be an amount (effective amount) effective to inhibit the activity of MGAT, and the amount is the subject of administration, the administration route.
  • the dose is about 0.3 mg to about 1 g / kg / day, preferably about 1 mg to about 500 mg / kg / day. What is necessary is just to administer.
  • the amount may be administered once a day, but may be administered 1 to 5 times a day, preferably 1 to 3 times a day, 2, 3, 4, 5, 6, 7 It may be administered once every day or more.
  • the MGAT inhibitor of the present invention can be used in combination with other anti-obesity agents, diabetes treatment agents, hyperlipidemia treatment agents and the like for the purpose of enhancing the effect.
  • MGAT inhibitor, fat absorption inhibitor, dyslipidemia treatment and / or prevention agent, obesity treatment and / or prevention agent or pharmaceutical composition and anti-obesity agent, diabetes treatment agent, hyperlipidemia treatment agent of the present invention When these are used in combination, the timing of these administrations is not particularly limited, and these may be administered simultaneously to administration subjects, or may be administered separately with a time difference.
  • ⁇ Manufacturing method The production method of the compound represented by the general formula (I) of the present invention is described below.
  • the compound of the present invention can be produced, for example, by the following production methods A and B.
  • Step a-1 In this step, Boc 2 O (ditertiary butyl dicarbonate) is added to compound (A1) in the presence of a suitable solvent and amine and stirred at room temperature to obtain (A2).
  • the solvent is preferably dichloromethane and the amine is preferably triethylamine. After the reaction, it is purified by extraction.
  • Step a-2 This step is a step of obtaining compound (A3) by heating compound (A2) in the presence of aqueous ammonia. After the reaction, it is extracted and purified by column chromatography.
  • Step a-3 This step is a step of obtaining (A4) by adding the corresponding isothiocyanate to compound (A3) in the presence of a suitable solvent and amine and heating. After the reaction, the reaction solution is concentrated and purified by crystallization.
  • Step a-4 In this step, compound (A4) is added with the corresponding alkyl halide (R 3 -Hal) in the presence of a suitable solvent and amine and stirred to obtain (A5). After the reaction, it is extracted and concentrated, followed by column chromatography or purification by crystallization.
  • Step a-5 In this step, compound (A5) is deprotected in the presence of a suitable solvent and acid catalyst to obtain (A6).
  • Step a-6 In this step, acrylic acid chloride is added to compound (A6) in the presence of a suitable solvent and base and stirred at room temperature to obtain (A7). After the reaction, extract, concentrate, and purify by crystallization.
  • Step a-7 In this step, compound (A7) is added with the corresponding amine in the presence of a suitable solvent and base, and heated and stirred at 80 ° C. to obtain (A8). After the reaction, the reaction solution is concentrated and purified by a reverse phase preparative column.
  • ⁇ Production method B> Among the compounds represented by the general formula (I), a compound (B2 below) in which R 1 is a methylene group and Y is —S— can be produced, for example, by the following production method.
  • Step b-1 This step is a step of obtaining (B1) by adding chloroacetyl chloride to compound (A6) in the presence of a suitable solvent and amine. After the reaction, it is used in [Step b-2] without purification.
  • Step b-2 In this step, compound (B1) is added with the corresponding amine in the presence of a suitable solvent and base, and heated and stirred at 80 ° C. to obtain (B2). After the reaction, the reaction solution is concentrated and purified by a reverse phase preparative column.
  • Diazabicycloundecene (56 ⁇ l) and indan-2-amine (24 ⁇ l) were added and stirred at 80 ° C. for 15 hours. Concentration under reduced pressure and purification by reverse phase preparative column gave Compound VIII (48 mg, 62%).
  • Examples 2 to 24 and 26 to 31 According to the method of Example 1, the compounds of Examples 2 to 24 and the compounds of Examples 26 to 31 shown in Table 1 below were synthesized.
  • the cells were suspended in a buffer containing a final concentration of 1 mM Tris-HCl (pH 7.4), 1 mM ethylenediaminetetraacetic acid, 1 mM dithiothreitol, 250 mM sucrose, and a complete protease inhibitor cocktail (Roche applied Science), and then a Teflon homogenizer. (As One) was crushed and centrifuged at 130 G for 10 minutes. This supernatant was further centrifuged at 100,000 G for 1 hour, and the pellet was obtained as microsomes containing the recombinant enzyme, and this was suspended at a protein concentration of about 800-1900 ⁇ g / ml and the MGAT recombinant enzyme solution. did.
  • the human MGAT2 recombinant enzyme solution was added to a final concentration of 0.67 ⁇ g / mL, and the reaction was started with a reaction solution volume of 150 ⁇ L.
  • the 14 C count was quantified using a scintillation luminescence counter (Perkin Elmer). 14 C-counting when no addition of test compounds A, WO2008 / 038768 Example No. 8 Compound 14 C-count upon addition of (Comparative Example 1) 10 [mu] M is defined as B, 14 upon addition of test compound
  • ⁇ 1- (CB) / (AB) ⁇ ⁇ 100 (%) was calculated as the human MGAT2 activity inhibition rate (the column of vs comparative example 1 in the table below).
  • inhibition rates at a plurality of concentrations were calculated for Examples 1 to 31 and Comparative Example 1, and a 50% inhibition concentration (IC 50 value) was obtained by 4-coefficient logistic regression analysis using XLFit (IDBS).
  • the compound of the present invention is a conventional compound due to its structure, in particular, having a structure of “—C ( ⁇ O) —R 1 —NH—” which is not found in conventional compounds.
  • MGAT2 inhibitory activity much higher than that of the compound of Comparative Example 1 was obtained. Therefore, the compound of the present invention is superior to conventional compounds as an MGAT2 inhibitor, has a fat absorption inhibitory action, and is considered to act effectively against dyslipidemia and obesity.
  • the compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof has an extremely high MGAT2 inhibitory activity as compared with conventional compounds. Therefore, it is excellent as an MGAT2 inhibitor and can be suitably used for suppression of fat absorption, treatment / prevention of dyslipidemia, and treatment / prevention of obesity. Therefore, it is very useful industrially.

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Abstract

　L'invention concerne un nouveau composé ayant une activité inhibitrice de MGAT-2 supérieure à celle des composés classiques, ledit composé étant représenté par la formule générale (I), ou un sel pharmaceutiquement acceptable de celui-ci.
PCT/JP2015/055768 2014-02-28 2015-02-27 Nouveau dérivé de tétrahydro-pyrido-pyrimidinone Ceased WO2015129845A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019013311A1 (fr) 2017-07-14 2019-01-17 塩野義製薬株式会社 Dérivé à cycle condensé ayant une activité inhibitrice de ｍｇａｔ２
US10335401B2 (en) 2015-12-21 2019-07-02 Shionogi & Co., Ltd. Non-aromatic heterocyclic derivative having MGAT2 inhibitory activity
WO2020145369A1 (fr) 2019-01-11 2020-07-16 塩野義製薬株式会社 Dérivé de dihydropyrazolopyrazinone présentant une activité inhibitrice sur mgat2
US11415205B2 (en) 2018-03-08 2022-08-16 Nsk Ltd. Internal-deflector type ball screw

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Publication number Priority date Publication date Assignee Title
WO2008038768A1 (fr) * 2006-09-28 2008-04-03 Dainippon Sumitomo Pharma Co., Ltd. Composé ayant une structure de pyrimidine bicyclique et composition pharmaceutique comprenant le composé
WO2012091010A1 (fr) * 2010-12-28 2012-07-05 大日本住友製薬株式会社 Dérivé de pyrimidine bicyclique
JP2014009165A (ja) * 2012-06-27 2014-01-20 Dainippon Sumitomo Pharma Co Ltd 二環性ピリミジン化合物
WO2014133134A1 (fr) * 2013-02-28 2014-09-04 味の素株式会社 Nouveau dérivé de tétrahydropyridopyrimidinone

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008038768A1 (fr) * 2006-09-28 2008-04-03 Dainippon Sumitomo Pharma Co., Ltd. Composé ayant une structure de pyrimidine bicyclique et composition pharmaceutique comprenant le composé
WO2012091010A1 (fr) * 2010-12-28 2012-07-05 大日本住友製薬株式会社 Dérivé de pyrimidine bicyclique
JP2014009165A (ja) * 2012-06-27 2014-01-20 Dainippon Sumitomo Pharma Co Ltd 二環性ピリミジン化合物
WO2014133134A1 (fr) * 2013-02-28 2014-09-04 味の素株式会社 Nouveau dérivé de tétrahydropyridopyrimidinone

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10335401B2 (en) 2015-12-21 2019-07-02 Shionogi & Co., Ltd. Non-aromatic heterocyclic derivative having MGAT2 inhibitory activity
WO2019013311A1 (fr) 2017-07-14 2019-01-17 塩野義製薬株式会社 Dérivé à cycle condensé ayant une activité inhibitrice de ｍｇａｔ２
KR20200029549A (ko) 2017-07-14 2020-03-18 시오노기 앤드 컴파니, 리미티드 Mgat2 저해 활성을 갖는 축합환 유도체
US11198695B2 (en) 2017-07-14 2021-12-14 Shionogi & Co., Ltd. Fused ring derivative having MGAT-2 inhibitory activity
EP4043463A1 (fr) 2017-07-14 2022-08-17 Shionogi & Co., Ltd Dérivé à cycle condensé ayant une activité inhibitrice de mgat2
US12024519B2 (en) 2017-07-14 2024-07-02 Shionogi & Co., Ltd. Fused ring derivative having MGAT-2 inhibitory activity
US12454533B2 (en) 2017-07-14 2025-10-28 Shionogi & Co., Ltd. Fused ring derivative having MGAT-2 inhibitory activity
US11415205B2 (en) 2018-03-08 2022-08-16 Nsk Ltd. Internal-deflector type ball screw
WO2020145369A1 (fr) 2019-01-11 2020-07-16 塩野義製薬株式会社 Dérivé de dihydropyrazolopyrazinone présentant une activité inhibitrice sur mgat2
KR20210114001A (ko) 2019-01-11 2021-09-17 시오노기 앤드 컴파니, 리미티드 Mgat2 저해 활성을 갖는 다이하이드로피라졸로피라지논 유도체
US12227509B2 (en) 2019-01-11 2025-02-18 Shionogi & Co., Ltd. Dihydropyrazolopyrazinone derivative having MGAT2 inhibitory activity

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