WO2016024598A1 - Nouveau dérivé tétrahydro pyridopyrimidinone - Google Patents

Nouveau dérivé tétrahydro pyridopyrimidinone Download PDF

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Publication number
WO2016024598A1
WO2016024598A1 PCT/JP2015/072805 JP2015072805W WO2016024598A1 WO 2016024598 A1 WO2016024598 A1 WO 2016024598A1 JP 2015072805 W JP2015072805 W JP 2015072805W WO 2016024598 A1 WO2016024598 A1 WO 2016024598A1
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Prior art keywords
group
dihydro
pyrido
compound
cyclobutylsulfanyl
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PCT/JP2015/072805
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English (en)
Japanese (ja)
Inventor
隆宏 小柴
大角　幸治
昌嗣 野口
飯野　幸生
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味の素株式会社
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Publication of WO2016024598A1 publication Critical patent/WO2016024598A1/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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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 linear C 1-6 alkylene group or a cyclic C 3-6 alkylene group, and if necessary, a deuterium atom, a halogen atom, a C 1-3 alkyl group, a C 1-3 haloalkyl group, C 1-3 alkylthio group, nitrile group, hydroxyl group, C 1-3 alkoxy group, C 1-3 haloalkoxy group, amino group, C 1-3 alkylamino group and C 2-6 dialkylamino group
  • substituents may be substituted, and when two C 1-3 alkyl groups are present as substituents on one carbon atom constituting R 2
  • the two C 1-3 alkyl groups may be bonded to each other to form a 3- to 7-membered
  • a 9-10 membered saturated or unsaturated bicyclic heterocyclic group (deuterium atom, halogen atom, hydroxyl group, amino group, C 1-3 alkyl group, C 3-6 cycloalkyl as necessary) Group, C 1-3 haloalkyl group, C 1-3 alkylthio group, nitrile group, C 1-3 alkoxy group, C 1-3 haloalkoxy group, C 1-3 alkylamino group, and C 2-6 dialkylamino group May be substituted with the same or different 1 to 5 substituents selected from: or may be substituted with a substituent selected from the following (a) to (f): (A) —C 1-3 alkylene-phenyl group (as required, deuterium atom, halogen atom, C 1-3 alkyl group, C 1-3 haloalkyl group, C 1-3 alkylthio group, nitrile group, C 1 -3 alkoxy groups, and optionally substituted with 1 to 5 substitu
  • R 1 is a linear C 1-3 alkylene group.
  • L is a phenyl group, a naphthyl group, a benzyl group, a 5- or 6-membered saturated or unsaturated heterocyclic group, or a 9 to 10-membered saturated or unsaturated bicyclic heterocyclic group (optionally) , Deuterium atom, halogen atom, hydroxyl group, amino group, C 1-3 alkyl group, C 3-6 cycloalkyl group, C 1-3 haloalkyl group, C 1-3 alkylthio group, nitrile group, C 1-3 alkoxy Substituted with 1 to 5 substituents which are the same or different selected from a group, a C 1-3 haloalkoxy group, a C 1-3 alkylamino group, and a C 2-6 dialkylamino group,
  • ⁇ 8> The compound or a pharmaceutically acceptable salt thereof according to any one of ⁇ 1> to ⁇ 7>, wherein R 3 is a C 3-6 alkyl group or a cycloalkyl group having 3 to 7 carbon atoms.
  • R 3 is a C 3-6 alkyl group or a cycloalkyl group having 3 to 7 carbon atoms.
  • Y is —S—, —O— or —NH—.
  • ⁇ 10> The compound according to ⁇ 1> or a pharmaceutically acceptable salt thereof selected from the group consisting of the following compounds.
  • a monoacylglycerol acyltransferase (MGAT) inhibitor comprising the compound according to any one of ⁇ 1> to ⁇ 10> or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a fat absorption inhibitor comprising as an active ingredient the compound according to any one of ⁇ 1> to ⁇ 10> or a pharmaceutically acceptable salt thereof.
  • a prophylactic and / or therapeutic agent for obesity comprising the compound according to any one of ⁇ 1> to ⁇ 10> or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a prophylactic and / or therapeutic agent for dyslipidemia comprising the compound according to any one of ⁇ 1> to ⁇ 10> or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a pharmaceutical composition comprising the compound according to any one of ⁇ 1> to ⁇ 10> 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 alkyl group and “C 1-6 alkylene group” mean an alkyl group having 1 to 6 carbon atoms and an alkylene group having 1 to 6 carbon atoms, respectively.
  • the “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.
  • the “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.
  • halogen atom is a concept including a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • alkyl group alkylene group
  • alkoxy group alkyl groups and alkoxy groups constituting haloalkyl groups, haloalkoxy groups, etc. It may be linear or branched.
  • heterocyclic group means a saturated or unsaturated ring (heterocycle) containing 1 to 3 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom.
  • a “bicyclic heterocyclic group” is a group in which one hydrogen atom is removed from a condensed ring obtained by condensing two rings including a heterocyclic ring.
  • the saturated heterocyclic group include groups in which one hydrogen atom has been removed from piperidine, piperazine, pyrrolidine, tetrahydrofuran and the like.
  • 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.
  • 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.
  • R 2 represents a linear C 1-6 alkylene group or a cyclic C 3-6 alkylene group (if necessary, a deuterium atom, a halogen atom, a C 1-3 alkyl group, C 1-3 haloalkyl group, C 1-3 alkylthio group, nitrile group, hydroxyl group, C 1-3 alkoxy group, C 1-3 haloalkoxy group, amino group, C 1-3 alkylamino group, and C 1-3 2-6 may be substituted with same or different 1-6 substituents selected from a dialkylamino group.
  • one of the carbon atoms constituting R 2 is a two C 1-3 alkyl groups When it has a substituent, the two C 1-3 alkyl groups may be bonded to each other to form a 3- to 7-membered ring together with the carbon atom).
  • R 2 is preferably a linear C 1-6 alkylene group, more preferably a linear C 1-5 alkylene group. That is, a methylene group, an ethylene group or an n-propylene group, an n-butylene group, and an n-pentylene group are particularly preferable.
  • the substituent is preferably a C 1-3 alkyl group.
  • the substituent is preferably a hydroxyl group.
  • the number of the substituents is preferably 1 to 3, more preferably 1 to 2.
  • X represents a single bond or —O—, —S—, or —NR 5 — (wherein R 5 represents a hydrogen atom, a C 1-6 alkyl group, a C 1-6 haloalkyl group). Represents).
  • X is preferably a single bond, —O—, —S— or —NH—, more preferably a single bond, —O— or —NH—, still more preferably a single bond or —O—, and most preferably —O—. preferable.
  • L represents a C 2-6 alkenyl group, a C 2-6 alkynyl group, a cycloalkyl group having 3 to 6 carbon atoms, a phenyl group, a naphthyl group, a benzyl group, 3 to 6-membered saturated or An unsaturated heterocyclic group, a 9 to 10-membered saturated or unsaturated bicyclic heterocyclic group (these groups as L are, if necessary, a deuterium atom, a halogen atom, a hydroxyl group, an amino group, C 1-3 alkyl group, C 3-6 cycloalkyl group, C 1-3 haloalkyl group, C 1-3 alkylthio group, nitrile group, C 1-3 alkoxy group, C 1-3 haloalkoxy group, C 1- Substituted with the same or different 1 to 5 substituents selected from 3 alkylamino groups, C 2-6 dialkylamino groups (ie
  • Phenyl group (deuterium atom, halogen atom, C 1-3 alkyl group, C 1-3 haloalkyl group, C 1-3 alkylthio group, nitrile group, C 1-3 alkoxy group, and C as required) ( It may be substituted with the same or different 1 to 5 substituents selected from 1-3 haloalkoxy groups)
  • L is a phenyl group, a naphthyl group, a benzyl group, a 5- or 6-membered saturated or unsaturated heterocyclic group, or a 9 to 10-membered saturated or unsaturated bicyclic heterocyclic group. It is preferable that it is a group having the following structure.
  • the position of bonding to X in the above group is not particularly limited as long as it can be bonded to X structurally. In the case of a bicyclic heterocyclic ring, any ring of the two condensed rings is not limited. May be bonded to X.
  • L is also preferably a C 2-6 alkynyl group (preferably ethynyl group) or a group having the following structure.
  • L is particularly preferably a phenyl group or a group obtained by removing one hydrogen atom from thiophene, furan, indole, indoline, thiazole, pyrazole, oxazole, or oxadiazole, and phenyl or thiophene.
  • a group obtained by removing one hydrogen atom from indole is more preferable, and a phenyl group is most preferable.
  • the following groups are also particularly preferable.
  • L has a substituent
  • the number of the substituent is 1 to 5, preferably 1 to 3, and more preferably 1 to 2.
  • L is a deuterium atom, halogen atom, C 1-3 alkyl group, C 3-6 cycloalkyl group, C 1-3 haloalkyl group, C 1-3 alkylthio group, nitrile. Is preferably substituted with the same or different 1 to 2 substituents selected from a group, a C 1-3 alkoxy group and a C 1-3 haloalkoxy group, or from the following (a) to (f) It is preferable that the selected substituent is mono-substituted.
  • (A) —C 1-3 alkylene-phenyl group (selected from deuterium atom, halogen atom, C 1-3 alkyl group, C 1-3 haloalkyl group, C 1-3 alkylthio group, nitrile group as necessary) (Preferably selected from C 1-3 haloalkyl groups, more preferably selected from CF 3 ), which may be substituted with the same or different 1 to 2, more preferably 1 substituent); (B) —C 1-3 alkylene-O—C 1-6 alkyl group (if necessary, the same or different one or two, more preferably one substituent selected from a deuterium atom and a halogen atom; Optionally substituted); (C) —C 1-3 alkylene-O-phenyl group (from deuterium atom, halogen atom, C 1-3 alkyl group, C 1-3 haloalkyl group, C 1-3 alkylthio group, nitrile group as necessary) Selected (preferably selected from C
  • the substituent for L is preferably a C 1-3 haloalkyl group, a C 1-3 haloalkoxy group, a halogen atom, a C 2-6 dialkylamino group, or a hydroxyl group (—OH), and —CF 3 , —O—CF 3 , a halogen atom, —N (CH 3 ) 2 , —OH, more preferably —CF 3 , —N (CH 3 ) 2 , —OH, Even more preferred is CF 3 .
  • L is the same or different 1 to 5 selected from phenyl group (—CF 3 , —N (CH 3 ) 2 and —OH (preferably —CF 3 ), preferably 1 to 2, more preferably May be substituted with one substituent), or is preferably the following group, more preferably a phenyl group substituted with one CF 3 , and one para-position A phenyl group substituted with CF 3 (4-trifluoromethylphenyl group) is particularly preferable.
  • Y is a single bond, —S—, —O—, or —NR 6 — (wherein R 6 is a hydrogen atom, a C 1-6 alkyl group, or a C 1-6 haloalkyl group. Represents).
  • R 6 is 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 cycloalkyl group having 3 to 8 carbon atoms, or a saturated or unsaturated heterocyclic group having 3 to 8 members (as R 3 These groups are optionally the same or different 1 to 3 selected from the group consisting of a deuterium atom, a halogen atom, a C 1-3 alkyl group, a C 1-3 haloalkoxy group, and a C 1-3 haloalkyl group. 7 may have a substituent).
  • R 3 is preferably a C 3-6 alkyl group or a cycloalkyl group having 3 to 7 carbon atoms, more preferably a cycloalkyl group having 3 to 6 carbon atoms, still more preferably a cycloalkyl group having 4 to 5 carbon atoms, The number 4 cycloalkyl group is particularly preferred.
  • 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 1 to 5 substituents selected from a hydroxyl group (—OH), a mercapto group (sulfanyl group) (—SH), and an amino group (—NH 2 ).
  • a phenyl group optionally selected from the group consisting of deuterium atom, halogen atom, C 1-3 alkyl group, C 1-3 haloalkyl group, C 1-3 alkoxy group, and C 1-3 haloalkoxy group
  • 1 to 4 substituents which may be the same or different (provided that the total number of substituents of the phenyl group of R 4 is 5 or less).
  • R 4 is more preferably a phenyl group having 1 to 3 at least one substituent selected from a hydroxyl group, a mercapto group, and an amino group, and is a phenyl group having 1 to 2 such substituents. Is more preferable, and a phenyl group having one such substituent is particularly preferable. Moreover, as at least 1 type of substituent selected from a hydroxyl group, a mercapto group, and an amino group, a hydroxyl group and / or an amino group are preferable, and a hydroxyl group is especially preferable.
  • R 4 is preferably a phenyl group having 1 to 5 hydroxyl groups, more preferably a phenyl group having 1 to 3 hydroxyl groups, and a phenyl group having 1 to 2 hydroxyl groups. Even more preferably, it is particularly preferably a phenyl group having one hydroxyl group. At least one substituent selected from a hydroxyl group, a mercapto group, and an amino group, particularly a hydroxyl group, may be bonded to any of the ortho, meta, and para positions of the phenyl group. It is preferably bonded and more preferably bonded to the ortho position.
  • R 4 is preferably a 2-hydroxyphenyl group, a 2-mercaptophenyl group, a 2-aminophenyl group, a 4-hydroxyphenyl group, a 4-mercaptophenyl group, or a 4-aminophenyl group.
  • a phenyl group, a 2-mercaptophenyl group or a 2-aminophenyl group is more preferable, and a 2-hydroxyphenyl group is particularly preferable.
  • R 4 is optionally selected from the group consisting of a deuterium atom, a halogen atom, a C 1-3 alkyl group, a C 1-3 haloalkyl group, a C 1-3 alkoxy group, and a C 1-3 haloalkoxy group. It may have 1 to 4 substituents which are the same or different (provided that the total number of substituents of the phenyl group of R 4 is 5 or less).
  • R 4 is the same or different selected from the group consisting of a deuterium atom, a halogen atom, a C 1-3 alkyl group, a C 1-3 haloalkyl group, a C 1-3 alkoxy group, and a C 1-3 haloalkoxy group.
  • the number of the substituent is preferably 1 to 4, preferably 1 to 2, and more preferably 1.
  • “The condition that the total number of substituents of the phenyl group of R 4 is 5 or less” means that the total number of substituents present in the phenyl group of R 4 , that is, the hydroxyl group, mercapto group, and amino group.
  • At least one selected substituent, and an optional deuterium atom, halogen atom, C 1-3 alkyl group, C 1-3 haloalkyl group, C 1-3 alkoxy group, and C 1 It means that the total of the same or different substituents selected from the group consisting of -3 haloalkoxy groups is 5 or less.
  • a compound selected from the group consisting of the following compounds is particularly preferable.
  • a compound selected from the group consisting of the following compounds is also particularly preferable as in the case of the above-mentioned three kinds of compounds.
  • Examples of the pharmaceutically acceptable salt of the compound represented by the general formula (I) include acid addition salts, alkali metal salts, alkaline earth metal salts, and salts as organic bases.
  • 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 an 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 converted to 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 a compound represented by the general 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 the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof may be an amount effective for inhibiting the activity of MGAT (effective amount).
  • administration route, target disease, symptom, etc. for example, when administered orally to humans, it is about 0.3 mg to about 1 g / kg / day, preferably about 0.5 mg to about 500 mg / kg / day.
  • Administered in an amount of a day more preferably an amount of about 1 mg to 200 mg / kg / day, even more preferably an amount of about 5 mg to 50 mg / kg / day, particularly preferably about 5 mg to 20 mg / kg / day. That's fine.
  • 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 days or more You may administer at the interval of once every the above day.
  • 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.
  • 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 method A, B, C, D or E.
  • the production method A, B, C, D or E the production of the reactive functional group in R 4 , hydroxy, amino, or thio group, is protected by using an appropriate protective group. Undesirable involvement of the reactive functional group in can be avoided. Protection and deprotection of hydroxy, amino, or thio groups with appropriate protecting groups can be accomplished using conventional methods, such as Protective Groups in Organic Synthesis, 4th Edition (TW Greene, P.G. M. Wuts, John Wiley & Sons Ins, 2006).
  • Step a-1 This step is a step of obtaining compound (A2) by reacting compound (A1) with Boc 2 O (ditertiary butyl dicarbonate) in the presence of an appropriate solvent and amine.
  • the solvent is preferably dichloromethane and the amine is preferably triethylamine.
  • purification is performed by extraction with ethyl acetate-water.
  • compound (A2) is heated in the presence of aqueous ammonia to obtain (A3). After the reaction, purification is performed by extraction with ethyl acetate-water.
  • 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. 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). The reaction solution is extracted and concentrated, followed by column chromatography, or after concentration and purified 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 This step is a step of obtaining (A7) by adding the corresponding acyl bromide to compound (A6) in the presence of a suitable solvent and amine.
  • the reaction solution is extracted and purified by column chromatography.
  • Step a-7 This step is a step of adding (A9) to compound (A7) in the presence of a suitable solvent and amine to obtain (A8).
  • the reaction solution is extracted and purified by column chromatography.
  • Step b-1 This step is a step of obtaining compound (B1) by reacting MeI (methyl iodide) with compound (A4) in the presence of a suitable solvent and base.
  • the solvent is preferably DMF (N, N-dimethylformamide) and the base is preferably potassium carbonate.
  • purification is performed by extraction with ethyl acetate-water.
  • compound (B1) is oxidized with m-CPBA (m-chloroperbenzoic acid) in the presence of a suitable solvent to obtain (B2). After the reaction, purification is performed by extraction with ethyl acetate-water.
  • Step b-3 This step is a step of obtaining (B3) by adding the corresponding amine to compound (B2) in the presence of a suitable solvent and base. The reaction solution is concentrated and purified by column chromatography.
  • Step b-4 In this step, compound (B3) is deprotected with a suitable solvent and acid catalyst to obtain (B4). The reaction mixture is concentrated and purified by crystallization.
  • Step b-5 This step is a step of obtaining (B5) by adding the corresponding acyl bromide to compound (B4) in the presence of a suitable solvent and base. The reaction solution is extracted and purified by column chromatography.
  • Step b-6 This step is a step of adding (A9) to compound (B5) in the presence of a suitable solvent and base to obtain (B6). The reaction solution is extracted and purified by column chromatography.
  • the compound (C2) in which Y is —S— and R 1 is —CH 2 CH 2 — can be produced, for example, by the following production method.
  • Step c-1 WSC (water soluble carbodiimide) and N-Boc-beta-alanine (N-Boc-beta-alanine) are added to compound (A6) in the presence of a suitable solvent and base.
  • the mixture is stirred at room temperature, then concentrated under reduced pressure, trifluoroacetic acid is added, and the mixture is concentrated under reduced pressure and purified by a reverse phase preparative column to obtain (C1).
  • Step c-2 In this step, compound (C1) is added with an appropriate aldehyde and sodium cyanoborohydride in the presence of an appropriate solvent and acid catalyst, stirred, concentrated under reduced pressure, and purified by column chromatography to obtain (C2). It is.
  • a compound in which R 1 is an ethylene group (—CH 2 CH 2 —) can be produced by, for example, the following production method in addition to the above production method.
  • Step d-1 a compound represented by the following general formula (III) is reacted with the compound represented by the following general formula (II) by adding acrylic acid chloride in the presence of a suitable solvent and base. It is a process to obtain.
  • the solvent include dichloromethane and tetrahydrofuran.
  • the base include diisopropylethylamine and triethylamine.
  • Step d-2 an alkylated amine represented by the formula L—X—R 2 —NH 2 (in the formula, in the presence of a suitable solvent and a base) is added to the obtained compound represented by the general formula (III).
  • L, X and R 2 have the general formula respectively the same L, and X and R 2 in which (I).) by reaction by adding, in the step of obtaining the above formula (I) compound is there.
  • the solvent include tetrahydrofuran and 1,4-dioxane.
  • the base include diazabicycloundecene and diisopropylethylamine.
  • the compound (D2) in which Y is —S— and R 1 is —CH 2 CH 2 — can be produced by the following production method.
  • Step d′-1 In this step, compound (A6) is added with acrylic acid chloride in the presence of a suitable solvent and base and stirred at room temperature. After the reaction, after extraction and drying, it is concentrated under reduced pressure and purified by a preparative column (D1 ).
  • Step d'-2 In this step, an appropriate alkylated amine is added to compound (D1) in the presence of an appropriate solvent and a base, and the mixture is heated and stirred at 80 ° C., concentrated under reduced pressure, and purified by a reverse phase preparative column (D2 ).
  • Step e-1 In this step, compound (A6) is added with WSC (water soluble carboimide), an appropriate carboxylic acid protected with a BOC group, and stirred at room temperature to obtain (E1) in the presence of an appropriate solvent and base. is there. After the reaction, it is concentrated under reduced pressure and purified by column chromatography. Examples of the solvent include dichloromethane and dimethylformamide. Examples of the base include diisopropylethylamine and triethylamine. [Step e-2] In this step, compound (E1) is deprotected in the presence of a suitable solvent and acid catalyst to give (E2). After the reaction, it is concentrated and purified by column chromatography.
  • WSC water soluble carboimide
  • Reference Examples 50 to 55, Reference Example 57, Reference Example 58 The synthesis of Reference Examples 50 to 55, Reference Example 57, and Reference Example 58 was performed according to the method of Reference Example 1. Instead of bromoacetyl bromide used in Reference Example 1, chloroacetyl chloride was used. Subsequently, the compounds of Reference Examples 50 to 55, Reference Example 57, and Reference Example 58 shown in the following table were synthesized by reacting with an appropriate amine.
  • step (vi) The crude product obtained in step (v), compound VII ′ (94 mg), WSC (water soluble carbodiimide) hydrochloride (53 mg) were dissolved in dichloromethane (2.0 mL), and diisopropylethylamine (74 ⁇ L) was dissolved. ) And stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure and proceeded directly to step (vii) without purification.
  • step (vii) The crude product obtained in step (vi) was dissolved in trifluoroacetic acid (1.0 mL) and stirred at room temperature for 15 minutes. The reaction solution was concentrated under reduced pressure and purified by reverse-phase preparative column chromatography (acetonitrile containing 0.1% trifluoroacetic acid / water containing 0.1% trifluoroacetic acid) to obtain compound VI ′ (77 mg, 50%).
  • Step (vii) The crude product obtained in step (vi) was dissolved in trifluoroacetic acid (1.0 mL) and stirred at room temperature for 15 minutes. The reaction solution was concentrated under reduced pressure and purified by reverse-phase preparative column chromatography (acetonitrile containing 0.1% trifluoroacetic acid / water containing 0.1% trifluoroacetic acid) to obtain compound VI ′ (77 mg, 50%).
  • step (xv) The crude product obtained in step (xv), compound VII ′ (239 mg) and WSC hydrochloride (141 mg) are dissolved in dichloromethane (1.5 mL), diisopropylethylamine (257 ⁇ L) is added, and the mixture is stirred at room temperature for 90 minutes. did. The reaction solution was concentrated under reduced pressure and proceeded directly to step (xvii) without purification.
  • step (xvii) The crude product obtained in step (xvi) was dissolved in trifluoroacetic acid (1.5 mL) and stirred at room temperature for 80 minutes. The reaction solution was concentrated under reduced pressure and purified by reverse phase preparative column chromatography (acetonitrile containing 0.1% trifluoroacetic acid / water containing 0.1% trifluoroacetic acid) to give compound XIV ′ (240 mg, 66%).
  • Examples 8 to 12 According to the method of Example 6, the compounds of Examples 8 to 12 shown in Table 4 below were synthesized.
  • 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 When the C count is C, ⁇ 1- (CB) / (AB) ⁇ ⁇ 100 (%) was calculated as the human MGAT2 activity inhibition rate (the column of vs comparative example 1 in the table below). .
  • the compounds of Reference Examples 1 to 24 which differ from the compounds of the general formula (I) of the present invention only in the structure of R 4 , are not found in the conventional compounds “—C ( ⁇ O) By having the structure of “—R 1 —NH—R 2 —X—”, an MGAT2 inhibitory activity much higher than that of the compound of Comparative Example 1 which is a conventional compound was obtained. Therefore, it is considered that the compounds of Reference Examples 1 to 24 are superior to conventional compounds as MGAT2 inhibitors, have a fat absorption inhibitory effect, and are effective against dyslipidemia and obesity.
  • the compounds of Reference Examples 25 to 60 which differ from the compound of the general formula (I) of the present invention only in the structure of R 4 , are not present in the conventional compounds: “—C ( ⁇ O) —R
  • MGAT2 inhibitory activity much higher than that of the compound of Comparative Example 1 which is a conventional compound was obtained. Therefore, the compounds of Reference Examples 25 to 60 are superior to conventional compounds as MGAT2 inhibitors, have a fat absorption inhibitory effect, and are considered to act effectively against dyslipidemia and obesity.
  • the compounds of Reference Examples 1 to 60 are conventional compounds by having the structure “—C ( ⁇ O) —R 1 —NH—R 2 —X—”. It was found that MGAT2 inhibitory activity much higher than that of a compound of Comparative Example 1 was obtained.
  • hMGAT2 After amplifying the hMGAT2 gene by PCR using pCMV6-XL5-hMOGAT2 (Origene, # SC128272) as a template, it was inserted into the EcoRI site and XhoI site of the multicloning site of pENTR1A (Life technologies), and Entry clone (pENTR1TR1). hMGAT2) was constructed.
  • the supernatant was further centrifuged at 100,000 g for 1 hour, and the pellet was obtained as microsomes containing the recombinant enzyme, which was suspended at a protein concentration of about 800-1900 ⁇ g / ml, and the hMGAT2 recombinant enzyme solution. did.
  • Human MGAT2 activity inhibitory action test Human MGAT2 inhibitory activity was evaluated in a 96-well format using a tube (BM BIO # P-8702-1). A test compound was added to a buffer solution containing 50 mM Tris-HCl (pH 7.4), 6 mM magnesium chloride, 2 mg / mL bovine serum albumin so that the final concentration of dimethyl sulfoxide was 0.3%, and then 2-monooleoylglycerol.
  • oleoyl CoA, 1-14 C-oleoyl CoA (Perkin Elmer), orlistat (SIGMA, # O4139) final respectively concentration 50 [mu] M, 50 [mu] M, 2.2 uM, was added to a 8.3MyuM, to 37 ° C. For 10 minutes. Ten minutes later, the hMGAT2 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 reaction was carried out at 37 ° C. for 30 minutes.
  • the compounds of Examples 1 to 3 had MGAT2 inhibitory activity in the same manner as the compound of Reference Example 5. Therefore, the compounds of Examples 1 to 3 also have the structure of “—C ( ⁇ O) —R 1 —NH—R 2 —X—” as in the compounds of Reference Examples 1 to 60. It can be seen that it has a much higher MGAT2 inhibitory activity than the compound of Example 1. That is, the compounds of Examples 1 to 3 are superior to conventional compounds as MGAT2 inhibitors, have a fat absorption inhibitory effect, and are considered to act effectively against dyslipidemia and obesity.
  • Human MGAT2 inhibitory activity was evaluated in a 96-well format using a tube (BM BIO # P-8702-1). A test compound was added to a buffer solution containing 50 mM Tris-HCl (pH 7.4), 6 mM magnesium chloride, 2 mg / mL bovine serum albumin so that the final concentration of dimethyl sulfoxide was 0.3%, and then 2-monooleoylglycerol.
  • oleoyl CoA, 1-14 C-oleoyl CoA (Perkin Elmer), orlistat (SIGMA, # O4139) final respectively concentration 50 [mu] M, 50 [mu] M, 2.2 uM, was added to a 8.3MyuM, to 37 ° C. For 10 minutes. Ten minutes later, the hMGAT2 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 reaction was carried out at 37 ° C. for 30 minutes.
  • the compounds of Examples 4 to 12 had MGAT2 inhibitory activity as the compounds of Examples 1 to 3. Therefore, the compounds of Examples 4 to 12 also have a structure of “—C ( ⁇ O) —R 1 —NH—R 2 —X—”, so that the MGAT2 inhibitory activity is much higher than that of the compound of Comparative Example 1. It can be seen that That is, the compounds of Examples 4 to 12 are superior to conventional compounds as MGAT2 inhibitors, have a fat absorption inhibitory effect, and are considered to act effectively against dyslipidemia and obesity.
  • the compound or vehicle (0.5% methylcellulose) was forcibly administered orally once a day from Day 1 to Day 22.
  • Body weight was measured every day, and body fat weight and lean body weight were measured using a quantitative NMR apparatus (EcoMRI, Hitachi Aloka Medical) on Day 21.
  • the percent body weight change (Day 23, Table 10), body fat weight (Day 21, Table 11), and lean body mass (Day 21, Table 12) are expressed as the difference in mean values between the compound administration group and the vehicle administration group.
  • the compound (3, 10, and 30 mg / kg) or vehicle (0.5% methylcellulose) was orally administered by gavage once a day from Day 1 to Day 22.
  • the body weight was measured every day, and body fat weight and lean body weight were measured using a quantitative NMR apparatus (EcoMRI, Hitachi Aloka Medical) on Day 19.
  • Percent body weight change (Day 22, Table 13), body fat weight (Day 19, Table 14), and lean body mass (Day 19, Table 15) are expressed as the difference in mean values between the compound administration group and the vehicle administration group.
  • the compound of Example 1 exhibited an excellent lipid inhibitory effect equivalent to that of the compound of Reference Example 5 at a dose 1/3 that of the compound of Reference Example 5. Since the compound of Reference Example 5 exhibits a lipid absorption action equivalent to or higher than that of the compound of Comparative Example 1 at a 1/3 dose of the compound of Comparative Example 1 (Table 16), the compound of Example 1 is It is considered that the lipid absorptive action equivalent to or higher than that of the compound of Comparative Example 1 is exhibited at a dose much smaller than that of the compound. In addition, the compounds shown in the compound group A can also be evaluated based on the test methods.
  • 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

La présente invention porte sur un composé représenté par la formule (I) ou sur un sel pharmaceutiquement acceptable de celui-ci.
PCT/JP2015/072805 2014-08-11 2015-08-11 Nouveau dérivé tétrahydro pyridopyrimidinone WO2016024598A1 (fr)

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Cited By (2)

* 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
US11198695B2 (en) 2017-07-14 2021-12-14 Shionogi & Co., Ltd. Fused ring derivative having MGAT-2 inhibitory activity

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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

Citations (3)

* 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
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 (3)

* 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
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 (2)

* 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
US11198695B2 (en) 2017-07-14 2021-12-14 Shionogi & Co., Ltd. Fused ring derivative having MGAT-2 inhibitory activity

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