Classifications

• • 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
  • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
• • 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
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• • 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
  • A61K31/4965—Non-condensed pyrazines
  • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
• • 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
  • A61K31/50—Pyridazines; Hydrogenated pyridazines
  • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
• • 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
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
• • 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
  • A61K31/527—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim spiro-condensed
• • 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
• • 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
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • 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
• • 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
  • C07D471/10—Spiro-condensed systems
• • 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
  • C07D471/12—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 three hetero rings
  • C07D471/20—Spiro-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/10—Spiro-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
  • C07D491/14—Ortho-condensed systems
  • C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
  • C07D491/20—Spiro-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

• the present invention relates to a compound having a monoacylglycerol acyltransferase 2 (monoacylglyceryl acyltransferase 2, hereinafter also referred to as MGAT2) inhibitory action, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the same.
• MGAT2 monoacylglycerol acyltransferase 2
• Body mass index is a simple index of height-to-weight ratio commonly used to classify an adult (age 15 or older) population or individual as overweight or obese. It is defined as the weight (kg / m 2 ) in kilograms divided by the square of the height in meters.
• BMI is 25kg / m 2 or more "overweight", and 30kg / m 2 or more as the "obesity”.
• the Japan Bariatrics Association defines BMI of 25 kg / m 2 or more as “obese”.
• MGAT As MGAT, three isoforms of MGAT1, MGAT2 and MGAT3 have been identified. Among these, MGAT2 and MGAT3 are highly expressed in the small intestine, and are considered to be involved in fat absorption in the small intestine. It has been reported by experiments with MGAT2 knockout mice that expression of MGAT2 in the small intestine is enhanced by high fat diet loading, and MGAT activity is increased (Non-patent Document 1). Furthermore, in MGAT2 knockout mice, suppression of weight gain by high fat diet loading, suppression of induction of insulin resistance, suppression of blood cholesterol elevation, suppression of fatty liver formation, etc. and enhancement of energy consumption have been confirmed (non-patent) Literature 2). So far, compounds having MGAT2 inhibitory activity have been reported (patent documents 1 to 19, non-patent documents 3 to 13), but there is no disclosure of the compounds of the present invention shown below.
• An object of the present invention is to provide a compound having MGAT2 inhibitory activity or a pharmaceutically acceptable salt thereof and a pharmaceutical composition containing them.
• the present inventors succeeded in synthesizing an excellent compound having MGAT2 inhibitory activity. That is, the present invention relates to the following.
• Ring B has the formula: (In the formula, each symbol is as defined above in [1] Or the pharmaceutically acceptable salt thereof.
• R 2a has the formula: (Wherein each symbol is as defined in the above [1]), The compound of the above-mentioned [1] or a pharmaceutically acceptable salt thereof, wherein R 2b is alkyl or haloalkyl.
• [7] The pharmaceutical composition of the above-mentioned [6], which has an MGAT2 inhibitory action.
• a method for treating or preventing a disease involving MGAT2 which comprises administering the compound according to any one of the above [1] to [5], or a pharmaceutically acceptable salt thereof.
• the compound according to the present invention has an MGAT2 inhibitory action, and is a preventive agent for obesity, metabolic syndrome, hyperlipidemia, hypertriglyceridemia, hyperVLDLemia, hyperlipidemia, diabetes or arteriosclerosis, And / or useful as a therapeutic agent.
• halogen includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
• a fluorine atom and a chlorine atom are preferred.
• alkyl includes straight or branched hydrocarbon groups having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and still more preferably 1 to 4 carbon atoms. Do. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl , Isooctyl, n-nonyl, n-decyl and the like.
• alkyl examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and n-pentyl. Further preferred embodiments include methyl, ethyl, n-propyl, isopropyl and tert-butyl.
• Alkylene is a linear or branched divalent hydrocarbon having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and still more preferably 1 to 4 carbon atoms. Include groups. For example, methylene, ethylene, propylene, tetramethylene, pentamethylene, hexamethylene and the like can be mentioned.
• aromatic carbocyclic group means a monocyclic or two or more cyclic aromatic hydrocarbon group.
• aromatic carbocyclic group phenyl, naphthyl, anthryl, phenanthryl and the like can be mentioned.
• Preferred embodiments of the "aromatic carbocyclic group” include phenyl.
• non-aromatic carbocyclic group means a monocyclic or two or more cyclic saturated hydrocarbon group or a cyclic non-aromatic unsaturated hydrocarbon group.
• the “two or more non-aromatic carbocyclic groups” also include those in which the ring in the above “aromatic carbocyclic group” is fused to a single ring or two or more non-aromatic carbocyclic groups.
• non-aromatic carbocyclic group also includes a group bridged as follows or a group forming a spiro ring.
• the monocyclic non-aromatic carbocyclic group preferably has 3 to 16 carbon atoms, more preferably 3 to 12 carbon atoms, and still more preferably 4 to 8 carbon atoms.
• the nonaromatic carbocyclic group having 2 or more rings preferably has 8 to 20 carbon atoms, and more preferably 8 to 16 carbon atoms.
• indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, fluorenyl and the like can be mentioned.
• the “aromatic heterocyclic group” means a monocyclic or bicyclic aromatic cyclic group having one or more identical or different hetero atoms selected from O, S and N in the ring. Do.
• the aromatic heterocyclic group having two or more rings also includes one in which the ring in the above "aromatic carbocyclic group” is fused to a monocyclic or two or more aromatic heterocyclic group.
• the monocyclic aromatic heterocyclic group preferably has 5 to 8 members, more preferably 5 or 6 members.
• pyrrolyl imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, triazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl and the like.
• the two-ring aromatic heterocyclic group is preferably 8 to 10 members, more preferably 9 members or 10 members.
• indolyl isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazole Ryl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridyl, thiazolopyridyl etc.
• aromatic heterocyclic group having 3 or more rings examples include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxatyinyl, phenoxazinyl, dibenzofuryl and the like.
• non-aromatic heterocyclic group is a monocyclic or two or more cyclic non-aromatic cyclic group having one or more identical or different hetero atoms optionally selected from O, S and N in the ring. Means a group.
• the nonaromatic heterocyclic group having two or more rings is a single ring or a nonaromatic heterocyclic group having two or more rings, and the above “aromatic carbocyclic group”, “nonaromatic carbocyclic group”, and And / or each of the rings in the "aromatic heterocyclic group” is condensed, and further, the ring in the above “aromatic heterocyclic group” is condensed to a monocyclic or two or more nonaromatic carbocyclic group Also include those that Furthermore, "non-aromatic heterocyclic group” also includes a group which is bridged as follows or a group which forms a spiro ring.
• the monocyclic non-aromatic heterocyclic group is preferably a 3- to 8-membered, more preferably 5- or 6-membered.
• the non-aromatic heterocyclic group having 2 or more rings is preferably 8 to 20 members, more preferably 8 to 10 members.
• indolinyl, isoindolinyl, chromanyl, isochromanyl and the like can be mentioned.
• substituent group ⁇ may mean that a carbon atom, a nitrogen atom or a sulfur atom at any position may be bonded to one or more groups selected from substituent group ⁇ .
• substituent group ⁇ may be substituted with substituent group ⁇ ”.
• the feature of the compound according to the present invention is that the ring A is condensed to a single ring such as dihydropyridone of the formula (I) to have an MGAT2 inhibitory action. Another feature is that the ring A is condensed to a single ring such as dihydropyridone, whereby the enone structure can be avoided and the toxicity can be suppressed.
• the compounds represented by the formula (I) are not limited to specific isomers, and all possible isomers (for example, keto-enol isomers, imine-enamine isomers, diastereoisomers, optical isomers , Rotamers, etc.), racemates or mixtures thereof.
• One or more of the hydrogen, carbon and / or other atoms of the compounds of formula (I) may be replaced by isotopes of hydrogen, carbon and / or other atoms, respectively.
• isotopes are 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 123 I and respectively.
• hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine are included.
• the compounds of formula (I) also encompass such isotopically substituted compounds.
• the isotopically substituted compounds are also useful as pharmaceuticals, and include all radioactive labels of the compounds of formula (I).
• the present invention also includes a "radiolabeling method" for producing the "radioactive label", and the "radioactive label” is useful as a research and / or diagnostic tool in metabolism pharmacokinetic study, binding assay. It is.
• Radioactive labels of the compounds of formula (I) can be prepared by methods well known in the art.
• a tritium labeled compound represented by the formula (I) can be prepared by introducing tritium into a specific compound represented by the formula (I) by a catalytic dehalogenation reaction using tritium.
• tritium gas is suitably reacted with a halogen-substituted precursor of a compound of formula (I) in the presence or absence of a base in the presence of a suitable catalyst such as Pd / C.
• a suitable catalyst such as Pd / C.
• Other suitable methods for preparing tritium labeled compounds can be referred to in "Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)".
• the 14 C-labeled compound can be prepared by using a raw material having 14 C carbon.
• an alkali metal eg, lithium, sodium, potassium etc.
• an alkaline earth metal eg, Calcium, barium, etc., magnesium, transition metals (eg, zinc, iron etc.)
• ammonia organic bases (eg, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, pyridine, picoline, Salts with quinoline etc.) and amino acids, or inorganic acids (eg, hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid etc.), and organic acids (eg, formic acid, acetic acid, propionic acid) , Trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, Maleic acid, fuma, sodium acetic acid, sodium, potassium etc.
• an alkaline earth metal eg, Calcium
• the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form a solvate (eg, hydrate etc.), co-crystal and / or crystal polymorph, and the present invention Also includes such various solvates, co-crystals and crystal polymorphs.
• the “solvate” may be coordinated with any number of solvent molecules (eg, water molecule etc.) with respect to the compound represented by the formula (I).
• solvent molecules eg, water molecule etc.
• the compound represented by formula (I) or a pharmaceutically acceptable salt thereof may be recrystallized to form a crystalline polymorph.
• “Co-crystal” means that the compound or salt of Formula (I) and the counter molecule are present in the same crystal lattice, and may be formed with any number of counter molecules.
• the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form a prodrug, and the present invention also encompasses such various prodrugs.
• Prodrugs are derivatives of the compounds of the present invention having chemically or metabolically degradable groups and are compounds which become pharmaceutically active compounds of the present invention by solvolysis or under physiological conditions in vivo.
• Prodrugs are compounds that are enzymatically oxidized, reduced, hydrolyzed, etc. under physiological conditions in vivo to be converted to compounds of formula (I), hydrolyzed by gastric acid, etc. The compound etc. which are converted into the compound shown are included. Methods for selecting and producing suitable prodrug derivatives are described, for example, in "Design of Prodrugs, Elsevier, Amsterdam, 1985". Prodrugs may themselves have activity.
• the compound of the formula (I) or a pharmaceutically acceptable salt thereof has a hydroxyl group, for example, a compound having a hydroxyl group and an appropriate acyl halide, an appropriate acid anhydride, an appropriate sulfonyl chloride, an appropriate Examples are prodrugs such as acyloxy derivatives and sulfonyloxy derivatives which are produced by reacting sulfonyl anhydride and mixed an hydride or by using a condensing agent.
• the compounds represented by the formula (I) according to the present invention can be produced, for example, by the general synthetic method shown below. Extraction, purification and the like may be carried out by ordinary organic chemistry experiments. The compounds of the present invention can be synthesized by referring to methods known in the art.
• the compound represented by the formula (I) according to the present invention (the following a5) can be produced, for example, by the following process.
• X 1 is chlorine, bromine, iodine, trifluoromethanesulfonate
• X 2 is chlorine, bromine, iodine; each symbol is as defined above
• the compound a3 can be obtained by reacting the compound a2 with a base in the compound a1.
• the base include triethylamine, diisopropylethylamine, sodium hydrogen carbonate, cesium carbonate, potassium carbonate and the like.
• the reaction temperature is 0 ° C to 100 ° C.
• the reaction time is 1 hour to 10 hours.
• Step 2 Compound a4 can be obtained by reacting compound a3 with a halogenating agent such as copper chloride or copper bromide, an acid, and an aqueous solution such as sodium nitrite.
• a halogenating agent such as copper chloride or copper bromide
• an acid such as sodium nitrite.
• the acid include hydrochloric acid and acetic acid.
• the reaction temperature is 0 ° C to 100 ° C.
• the reaction time is 1 hour to 10 hours.
• Step 3 The compound a4 can be obtained by reacting the compound a4 with a boronic acid or a boronic ester or a trialkylstannane in the presence of a metal catalyst and a base.
• metal catalyst palladium acetate, bis (dibenzylideneacetone) palladium, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium (II) dichloride, bis (tri-tert-butylphosphine) palladium etc. It can be used at 0.001 to 0.5 molar equivalent relative to the compound a4.
• Examples thereof include hydrogen potassium and the like, which can be used at 1 to 10 molar equivalents relative to the compound a4.
• the boronic acid or boronic ester or trialkylstannane can be used at 1 to 10 molar equivalents relative to the compound a4.
• the reaction temperature is 20 ° C. to the reflux temperature of the solvent, optionally under microwave irradiation.
• the reaction time is 0.1 to 48 hours, preferably 0.5 to 12 hours.
• the reaction solvent may, for example, be tetrahydrofuran, toluene, DMF, dioxane, water or the like, which may be used alone or in combination.
• a compound a5 having an amine or imine or cyanide at R 4a can be synthesized by reacting the compound a4 with an amine or imine or potassium cyanide or the like.
• R 4a is carbonylamino, sulfonylamino or the like, it can be synthesized by adding various functional groups to the compound a 3.
• the compound a3 can be produced, for example, by the following production method. (In the formula, each symbol is as defined above.)
• Step 1 Compound a6 can be obtained by reacting compound a1 with hydrazine hydrate. The reaction temperature is 0 ° C to 100 ° C. The reaction time is 1 hour to 20 hours. As the reaction solvent, methanol, ethanol, tetrahydrofuran and the like can be mentioned.
• Step 2 Compound a6 can be obtained by reacting compound a6 with a base and a halide.
• sodium hydrogencarbonate, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, sodium hydride and the like can be mentioned.
• the reaction temperature is 0 ° C to 100 ° C.
• the reaction time is 1 hour to 10 hours.
• a reaction solvent tetrahydrofuran, dichloromethane, dimethylformamide and the like can be mentioned.
• the compound according to the present invention has an MGAT2 inhibitory action and is a preventive agent for obesity, metabolic syndrome, hyperlipidemia, hypertriglyceridemia, hyperVLDLemia, hyperlipidemia, diabetes, arteriosclerosis and the like. Or useful as a therapeutic agent.
• the compounds of the present invention have not only MGAT2 inhibitory activity but also utility as pharmaceuticals, and possess any of the following or all of the excellent features. a) Metabolic stability is high. b) show high solubility. c) There is little concern about phototoxicity. d) Concern about hepatotoxicity is small. e) There is little concern about nephrotoxicity. f) There is little concern of cardiovascular toxicity. g) There is little concern about digestive tract disorders.
• the pharmaceutical composition of the present invention can be administered orally or parenterally.
• the method of parenteral administration includes percutaneous, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, transnasal, instillation, instillation, intravaginal administration and the like.
• a solid preparation for internal use for example, tablet, powder, granule, capsule, pill, film, etc.
• liquid for internal use for example, suspension, emulsion, elixir, syrup
• a medicine for example, a limonade, an alcoholic liquor, an aromatic liquid, an extract, a decoction, a tincture and the like.
• the tablets may be sugar coated tablets, film coated tablets, enteric coated tablets, sustained release tablets, troche tablets, sublingual tablets, buccal tablets, chewable tablets or orally disintegrating tablets and the powder and granules are dry syrup
• the capsule may be a soft capsule, a microcapsule or a sustained release capsule.
• injections, drops, external preparations for example, eye drops, nose drops, ear drops, aerosols, inhalants, lotions, infusates, injections, gargles, enemas
• the injection may be an emulsion of O / W, W / O, O / W / O, W / O / W, etc.
• the dose of the pharmaceutical composition of the present invention is usually 0.05 to 100 mg / mg when orally administered. It is kg / day, preferably in the range of 0.1 to 10 mg / kg / day. In the case of parenteral administration, although it largely depends on the administration route, it is usually 0.005 to 10 mg / kg / day, preferably 0.01 to 1 mg / kg / day. It may be administered once to several times a day.
• the dose of the concomitant drug can be appropriately selected based on the dose clinically used.
• the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, condition, combination and the like. For example, when the administration subject is a human, 0.01 to 100 parts by weight of the concomitant drug may be used based on 1 part by weight of the compound of the present invention.
• the pharmaceutical composition of the present invention is also used for obesity (but only for cases with both type 2 diabetes and dyslipidemia and having a BMI of 25 kg / m 2 or more despite diet and exercise). It is valid.
• the pharmaceutical composition of the present invention is also effective against severe obesity in which the effects of a pre-applied diet and exercise therapy are insufficient.
• the pharmaceutical composition of the present invention can also be used in combination with other anti-obesity agents (pharmaceutical compositions containing compounds having an anti-obesity action, agents that can be used for weight management in obesity and obesity, etc.) .
• pharmaceutical compositions containing compounds having an anti-obesity action for weight management in obesity and obesity, etc.
• it can be used for the prevention and / or treatment of obesity, weight management in obesity and the like.
• a pharmaceutical composition containing the compound of the present invention in combination with a pharmaceutical composition containing a compound having an anti-obesity effect it can be used for prevention and / or treatment of obesity, weight management in obesity, etc. it can.
• the administration therapy of the pharmaceutical composition of the present invention can be used in combination with diet therapy, drug therapy, exercise and the like.
• DIEA N, N-diisopropylethylamine
• DMA dimethylacetamide
• DMF N, N-dimethylformamide
• DMSO dimethylsulfoxide
• HATU O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyl Uronium hexafluorophosphate
• Example 1 Step 1 Known compound 1 (WO2015069224A1) (54.7 mg, 0.142 mmol) was dissolved in tetrahydrofuran (1.1 mL), phenylhydrazine (28 ⁇ L, 0.28 mmol) was added under ice-cooling and stirred for 20 minutes. To the reaction solution was added DIEA (50 ⁇ L, 0.28 mmol) under ice-cooling, and the mixture was stirred at room temperature for 3 hours, and further stirred at 70 ° C. for 1 hour. The solvent of the reaction solution was evaporated under reduced pressure, and the obtained residue was purified by column chromatography (chloroform-methanol) to obtain compound 2 (59.4 mg, yield 92%).
• Example 2 Step 1 Compound 1 (1.0 g, 2.60 mmol) was dissolved in ethanol (15 mL), hydrazine monohydrate (0.65 ml, 13.0 mmol) was added, and the mixture was stirred at room temperature to 80 ° C. for 18 hours. At room temperature, the reaction mixture was added with aqueous sodium bicarbonate, extracted with chloroform, and dried over sodium sulfate. The solvent was distilled off under reduced pressure and suspension purification (ethyl acetate / hexane) gave compound 3 (890 mg, yield 90%).
• Step 3 The crude product of compound 4 (0.24 mmol) is dissolved in toluene (1 mL), 2- (methanesulfonyl) acetic acid (66.2 mg, 0.48 mmol) and N, N'-dicyclohexylcarbodiimide (99.0 mg, 0 .48 mmol) was added at room temperature and stirred for 1 hour. Water was added to the reaction mixture at room temperature, extracted with ethyl acetate, and dried over sodium sulfate.
• Example 3 Step 1 Dissolve compound 3 (719 mg, 1.89 mmol) in DMF (7 mL), add 2-cyclopropylethyl methanesulfonate (466 mg, 2.84 mmol) and potassium carbonate (1.31 g, 9.45 mmol), 80 Stir at 5 ° C for 5 hours. Water was added to the reaction mixture at room temperature, extracted with chloroform, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by column chromatography (ethyl acetate) to give compound 5 (358 mg, yield 42%).
• Step 2 Compound 5 (2.30 g, 5.13 mmol) and copper dichloride (1.38 g, 10.3 mmol) are dissolved in acetic acid (7 mL) and concentrated hydrochloric acid (11 mL) and sodium nitrite (460 mg, 6.67 mmol) The aqueous solution of (1 mL) was added dropwise under ice-cooling and stirred for 45 minutes under ice-cooling. The reaction solution was extracted with chloroform, and the organic layer was washed with saturated aqueous ammonium chloride solution and 2M aqueous sodium carbonate solution, and then dried over sodium sulfate.
• Step 3 Compound 6 (1.57 g, 3.36 mmol) was dissolved in DMA (16 ml), potassium cyanide (678 mg, 10.4 mmol) was added, and the mixture was stirred at 200 ° C. for 3 hours under microwave irradiation. The reaction mixture was allowed to cool to room temperature, saturated aqueous sodium hydrogen carbonate solution and water were added, and the aqueous layer was extracted with hexane-ethyl acetate (2: 1). The organic layer was washed with water and saturated brine and then dried over sodium sulfate. The solvent was distilled off under reduced pressure to give a crude product of compound 7 (1.46 g).
• Step 4 The crude product of compound 7 (212 mg), sodium azide (150 mg, 2.31 mmol) and ammonium chloride (124 mg, 2.31 mmol) are suspended in DMF (4.2 mL) and water (0.4 mL), 140 Stir at ⁇ RTIgt; C ⁇ / RTI> for 3 hours.
• the reaction solution is allowed to cool to room temperature, aqueous citric acid solution is added, and the aqueous layer is extracted with ethyl acetate.
• the organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure.
• the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to give compound I-24 (162 mg, two-step yield 66%).
• Example 4 Step 1 Compound 7 (1.46 g, 3.18 mmol) is dissolved in tetohydrofuran (6 mL) and methanol (6 mL), 5N aqueous solution of sodium hydroxide (6.4 mL, 3.2 mmol) is added, and the solution is irradiated with microwave 120 Stir at 75 ° C for 75 minutes. The reaction solution was returned to room temperature, 2N hydrochloric acid (30 mL) was added, the aqueous layer was extracted with chloroform, and the organic layer was dried over sodium sulfate.
• Step 2 Compound 2 (486 mg, 1.02 mmol) and carbonyldiimidazole (495 mg, 3.05 mmol) were dissolved in tetrahydrofuran (5 mL) and stirred at 70 ° C. for 100 minutes. The reaction mixture was allowed to cool to room temperature, methanesulfonic acid amide (484 mg, 5.09 mmol) and diazabicycloundecene (0.77 mL, 5.1 mmol) were added, and the mixture was stirred at room temperature for 14 hours.
• Example 5 Step 1 Compound 7 (23.1 mg, 50.4 ⁇ mol) and 5% palladium carbon (23 mg) were suspended in methanol (1.5 mL) and concentrated hydrochloric acid (0.2 mL), and stirred at room temperature for 4 hours under a hydrogen atmosphere . The reaction mixture was filtered, and the solvent was evaporated under reduced pressure to give compound 9 (24.9 mg, yield 99%).
• Step 2 Compound 9 (6.0 mg, 12 ⁇ mol) was suspended in tetrahydrofuran (0.7 mL), acetic anhydride (6 ⁇ L, 0.06 mmol) and triethylamine (17 ⁇ L, 0.12 mmol) were added and stirred at room temperature for 20 minutes. After adding methanol (2 mL), the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to give compound I-10 (4.6 mg, yield 76%).
• Example 11 Step 1 Tetraethoxy titanium (141 mL, 666 mmol), compound 51 (100 g, 444 mmol) in tetrahydrofuran (250 mL) in a solution of (R) -2-methylpropane-2-sulfinamide (134 g, 1.11 mol) in toluene (500 mL) A toluene (250 mL) solution was added and stirred at 90 ° C. for 12 hours. To the reaction mixture was added saturated aqueous ammonium chloride solution at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution and then dried over anhydrous sodium sulfate.
• Step 2 Methyl acetate (26.5 mL, 333 mmol) was added to 1 mol / L lithium hexamethyldisilazide tetrahydrofuran solution (334 mL, 333 mmol) at -78 ° C. and stirred for 1 hour.
• a solution of titanium triisopropoxide chloride (110 g, 424 mmol) in tetrahydrofuran (250 mL) was added dropwise at -78.degree. C. and stirred for 2 hours.
• a solution of compound 52 (50.0 g, 151 mmol) in tetrahydrofuran (250 mL) was added dropwise to the reaction solution at ⁇ 78 ° C.
• Step 3 Compound 53 (1.4 g, 3.46 mmol) in dioxane (15 mL), bis (pinacolato) diboron (1.32 g, 5.19 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium (Pd) II)
• Dichloride Dichloromethane complex (1: 1) (0.141 g, 0.17 mmol) and potassium acetate (1.02 g, 10.4 mmol) were added and stirred at 100 ° C. for 4 hours.
• 30% aqueous hydrogen peroxide (1.96 mL, 17.3 mmol
• reaction solution is added with 10% aqueous citric acid solution, extracted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. Purification by silica gel column chromatography (hexane-ethyl acetate) gave compound 54 (1.23 g, yield 84%).
• Step 4 To a solution of compound 54 (545 mg, 1.29 mmol) in methanol (1.1 mL) was added 4 mol / L hydrochloric acid in dioxane (0.64 mL, 2.57 mmol), and the mixture was stirred at room temperature for 1 hour.
• Step 5 To a solution of compound 55 (497 mg, 1.29 mmol) in methanol (2.5 mL) was added 28% sodium methoxide methanol solution (993 mg, 5.15 mmol), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture were added 2 mol / L aqueous hydrochloric acid solution (6 mL) and water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. After concentration, the resulting residue was dissolved in ethyl acetate and back extracted with saturated aqueous sodium bicarbonate.
• Step 6 To a solution of compound 56 (500 mg, 1.41 mmol) in dichloroethane (5 mL) was added a solution of phosphoryl chloride (0.152 mL, 1.69 mmol) and DMF (0.136 mL, 1.70 mmol) in dichloroethane (5 ml) at room temperature Stir for 75 hours.
• Step 8 In a solution of compound 58 (430 mg, 0.94 mmol) in dichloromethane (5 mL), a solution of 2- (methanesulfonyl) acetyl chloride (3.74 mmol) in dichloromethane (3 ml) and pyridine (0.303 ml, 3.74 mmol) at 0 ° C. And stirred for one and a half hours. At room temperature, water was added, extracted with ethyl acetate, and dried over magnesium sulfate.
• Example 12 Step 1 To compound 51 (1.75 g, 7.69 mmol) was added (S) -2-methylpropane-2-sulfinamide (1.03 g, 8.45 mmol) and tetraethoxytitanium (3.22 mL, 6 mmol), and the mixture was heated to 100 ° C. And stirred for 2 and a half hours. The reaction solution was diluted with ethyl acetate and water, and extracted with ethyl acetate.
• Step 2 Tetrahydrofuran (15 mL) and methyl acetate (0.72 mL, 9.01 mmol) were added to 1 mol / L lithium hexamethyldisilazide tetrahydrofuran solution (9.01 mL, 9.01 mmol) at -78 ° C. and stirred for 30 minutes.
• the reaction solution was added dropwise with a 1 mol / L solution of titanium triisopropoxide chloride in hexane (11.3 mL, 11.3 mmol) at ⁇ 78 ° C. and stirred for 20 minutes.
• Step 3 Bis (pinacolato) diboron (341 mg, 1.34 mmol), potassium acetate (359 mg, 3.66 mmol) and [1,1'-bis in a solution of compound 60 (512 mg, 1.22 mmol) in 1,4-dioxane (5 mL) (Diphenylphosphino) ferrocene] palladium (II) dichloride Dichloromethane adduct (19.9 mg, 0.024 mmol) was added, and nitrogen substitution was repeated three times under reduced pressure, and the mixture was heated under reflux for 3 hours. After cooling to room temperature, insolubles are filtered through Celite and the solvent is distilled off under reduced pressure.
• Step 4 Compound 61 (380 mg, 1.11 mmol) in DMF (1.5 mL), 2,2,2-trifluoroethyl trifluoromethanesulfonate (310 mg, 1.34 mmol) and potassium carbonate (185 mg, 1.34 mmol) And stirred at room temperature for 14 hours, then warmed to 60 ° C. and further stirred for 2 hours.
• reaction solution is diluted with ethyl acetate and water, and the organic layer is washed with water, and then the solvent is evaporated away under reduced pressure, and a solution of the obtained residue in methanol (2 mL) solution of 4 mol / L hydrochloric acid in dioxane (0.557 mL, 2 .23 mmol) was added and stirred at room temperature for 1 hour.
• Step 6 N-dimethylformamide (63.5 mg, 0.869 mmol) and phosphorus oxychloride (133 mg, 0.869 mmol) in a suspension of compound 63 (308 mg, 0.869 mmol) in 1,2-dichloroethane (6.2 mL) ) And stirred at room temperature for 18.5 hours. Water was added to the reaction solution, and the precipitated solid was collected by filtration to give compound 64 (312 mg, yield 96%).
• Step 7 Hydrazine monohydrate (225 mg, 3.35 mmol) was added to a solution of compound 64 (500 mg, 1.34 mmol) in tetrahydrofuran (4 mL), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, extraction was performed with ethyl acetate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to give compound 65 (432 mg, yield 87%).
• Step 9 To a solution of compound 67 (137 mg, 0.28 mmol) in toluene (2 mL), 2- (methanesulfonyl) acetic acid (191 mg, 1.38 mmol) and N, N'-diisopropylcarbodiimide (0.22 ml, 1.38 mmol) at room temperature And stirred for 3 hours. Water was added under room temperature, extraction was performed with ethyl acetate, and the organic layer was washed with saturated aqueous sodium bicarbonate, and then the solvent was evaporated under reduced pressure.
• Example 13 Step 1 To a solution of compound 53 (5.50 g, 13.6 mmol) in methanol (60 mL) was added 4 mol / L hydrochloric acid in dioxane (3.40 mL, 13.6 mmol), and the mixture was stirred at room temperature for 1 hour.
• Step 3 To a solution of compound 69 (2.00 g, 5.97 mmol) in dichloroethane (20 mL), DMF (4.64 mL, 59.7 mmol) and phosphoryl chloride (0.61 mL, 6.56 mmol) were added and stirred at room temperature for 19 hours . Water was added to the reaction mixture, and the mixture was extracted with chloroform, washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
• Step 4 To a solution of compound 70 (250 mg, 0.71 mmol) in ethanol (5 mL) was added 2-hydrazinyl-5-methylpyridine hydrochloride (135 mg, 0.85 mmol) and sodium hydrogen carbonate (148 mg, 1.77 mmol), and 70 ° C. And stirred for one and a half hours. Water is added to the reaction mixture, and the mixture is extracted with chloroform, dried over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure, and diisopropyl ether is added to the obtained residue to powderize, whereby compound 71 (237 mg, yield 76) %) Got.
• Step 5 A solution of compound 71 (100 mg, 0.23 mmol) in toluene (2 mL) and water (0.4 mL) was combined with potassium cyclopropyl trifluoroborate (101 mg, 0.68 mmol), [1,1′-bis (di-tert-) Butyl phosphino) ferrocene] palladium (II) dichloride (0.148 g, 0.227 mmol) and cesium carbonate (0.222 g, 0.681 mmol) were added and stirred at 100 ° C. for 3 hours.
• Step 6 A solution of compound 72 (20.4 mg, 0.051 mmol) in dichloromethane (1 mL), a solution of 2- (methanesulfonyl) acetyl chloride (0.20 mmol) in dichloromethane (0.3 ml) and pyridine (0.016 ml, 0.20 mmol) ) was added at 0 ° C. and stirred for 3 hours. Water was added to the reaction mixture at room temperature, extracted with ethyl acetate, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol, amino silica gel) to give compound II-168 (14.2 mg, 54%).
• Example 14 Step 1 To a solution of (R) -2-methylpropane-2-sulfinamide (631 mg, 5.21 mmol) in toluene (2.5 mL) was added tetraethoxytitanium (0.654 mL, 3.12 mmol), and Compound 73 (384 mg, A solution of 2.08 mmol) in toluene (2.5 mL) was added and stirred at 100 ° C. for 3 hours. To the reaction solution were added an aqueous citric acid solution and ethyl acetate at room temperature, and the insolubles were filtered and extracted with ethyl acetate.
• Step 2 Tetrahydrofuran (1 mL) and methyl acetate (0.178 mL, 2.23 mmol) were added to 1 mol / L lithium hexamethyldisilazide tetrahydrofuran solution (2.23 mL, 2.23 mmol) at -78 ° C. and stirred for 1 hour. Thereafter, 1 mol / L titanium triisopropoxide chloride in hexane (2.98 mL, 2.98 mmol) was added dropwise at ⁇ 78 ° C. and stirred for 30 minutes. Thereafter, a solution of compound 74 (428 mg, 1.49 mmol) in tetrahydrofuran (1 mL) was added dropwise at ⁇ 78 ° C.
• Step 3 To a solution of compound 75 (305 mg, 0.85 mmol) in methanol (2.6 mL) was added 4 mol / L hydrochloric acid in dioxane (0.44 mL, 1.77 mmol), and the mixture was stirred at 0 ° C. for 1 hour. The solvent of the reaction solution is evaporated under reduced pressure, and the obtained residue is dissolved in tetrahydrofuran (2.5 ml), 2-cyanoacetic acid (108 mg, 1.27 mmol), HATU (482 mg, 1.27 mmol) and triethylamine (0 Add .29 mL, 2.11 mmol) and stir at room temperature for 4 hours.
• Step 4 To a solution of compound 76 (393 mg, 1.21 mmol) in methanol (4 mL) and tetrahydrofuran (1 mL) was added 1 mol / L sodium methoxide methanol solution (2.6 mL, 2.6 mmol), and the mixture was stirred at room temperature for 7 hours. A 2 mol / L aqueous hydrochloric acid solution (1.3 mL) was added to the reaction solution, methanol was added to the residue obtained after concentration, insolubles were removed by filtration, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the obtained residue to make a powder, and compound 77 (213 mg, 60%) was obtained.
• II-276 is an optically active compound although no stereochemical structure determination has been performed.
• RT in the table represents the retention time (minutes) in LC / MS (liquid chromatography / mass spectrometry), and “MS” represents the mass (M + H) in LC / MS Indicated, “LCMS Method” represents any of the following measurement conditions of LC / MS.
• Preparation Example 1 (Preparation of Recombinant Human MGAT2) The full-length human MGAT2 gene to which Flag-tag was added at the N-terminus was inserted into pFastBac (manufactured by Invitrogen). According to the protocol of Bac-to-Bac baculovirus expression system (manufactured by Invitrogen), recombinant baculovirus was produced and Sf-9 cells were infected. The collected cells were sonicated and then the membrane fraction was collected by centrifugation. The expression was confirmed by Western blot analysis with an anti-Flag antibody, and used as a recombinant human MGAT2 enzyme solution.
• Test Example 1 Measurement of Human MGAT2 Inhibitory Activity
• Assay buffer 100 mmol / L phosphate buffer (pH 7.4) containing 2 mmol / L DTT
• a Corning polystyrene 384-well microplate into which 0.2 ⁇ L of each compound of the present invention in DMSO was dispensed
• Add 5 ⁇ L of the prepared enzyme solution and 5 ⁇ L of substrate solution 100 mmol / L phosphate buffer (pH 7.4), 30 ⁇ mol / L 2-Oleoylglycerol, 10 ⁇ mol / L Oleoyl-CoA) in the wet box after stirring and centrifuging Incubation was for 1 hour at room temperature.
• the reaction was stopped by adding 50 ⁇ L of a stop solution (containing 0.2 ⁇ mol / L Diolein-d5, 0.4% formic acid and 50% isopropanol) containing Internal Standard (IS) to a plate made by Shimadzu GLC. After sealing, they were stirred and centrifuged, and measurement was performed by electrospray ionization using RapidFire 360 and Agilent 6550 Q-TOF mass spectrometer.
• the reaction product (P) Diolein of substrate 2-oleoylglycerol and ammonium adduct ion of IS were detected, peak intensity ratio P / IS was calculated using the peak height, and the inhibitory activity was evaluated.
• the inhibitory activity is defined as Control (+) / Control (-) with or without enzyme addition, and the inhibition ratio is 0% and 100% inhibition respectively, and the peak intensity ratio P / IS when the invention compound is added is Sample It calculated with TIBCO Spotfire (made by TIBCO Software) according to the following formula.
• Inhibitory activity (%) [1- ⁇ Sample-Control (-) ⁇ / ⁇ Control (+)-Control (-) ⁇ ] * 100
• the inhibitory activity results of each of the compounds of the present invention are shown in the following table.
• the IC 50 (nM) in the table indicates the concentration exhibiting 50% enzyme inhibition.
• Test Example 2 (metabolic stability test) A commercially available pooled human liver microsome and the compound of the present invention were reacted for a certain period of time, the residual rate was calculated by comparing the reaction sample and the unreacted sample, and the degree of metabolism of the compound of the present invention in the liver was evaluated.
• the compound of the present invention in the supernatant of the centrifugation was quantified by LC / MS / MS, and the remaining amount of the compound of the present invention after reaction was calculated assuming that the amount of compound at the time of 0 minutes reaction was 100%.
• the residual rate at a compound concentration of 0.5 ⁇ mol / L is shown.
• Test Example 4 As an in vitro phototoxicity test, an erythrocyte light hemolysis test (Wolfgang JW Pepe et al., ATLA29, 145-162, 2001), which is an evaluation method using action on biological membranes and photoperoxidation as an index, was performed. In this method, a mixed solution (concentration: 0.1 to 0.0008%) obtained by adding 2.5% (v / v) of sheep erythrocyte liquid to a prepared solution of the compound of the present invention using dimethylsulfoxide as a medium is used. Using.
• the absorbance obtained from the compound of the present invention is the value obtained by subtracting the absorbance of the medium with light and without irradiation.
• the light hemolysis rate was determined from the difference between the light irradiation and the non-irradiated absorbance (540 nm), and for light peroxidation, the change amount of the light irradiation and the non-irradiated absorbance (630 nm) was determined.
• the absorbance (540 nm) obtained from 2.5% (v / v) sheep red blood cell fluid forcibly hemolyzed using distilled water was used as a standard for the light hemolysis rate 100%.
• Test example 5 The number of cells after compound exposure was automatically measured using a cell image analyzer, Toxinsight (Thermofisher Scientific), and the cytotoxicity of the compound of the present invention was evaluated.
• HepG2 cells derived from human hepatoma cells
• the compound solution was added to each well.
• a DMSO solution containing the compound of the present invention maximum concentration is set to 50 ⁇ mol / L and 5-fold dilution by 2-fold common ratio, minimum concentration is about 3.1 ⁇ mol / L
• DMSO only solution as negative control
• Camptothecin solution was used as a positive control.
• a DMSO solution of the compound of the present invention, a negative control solution, or a positive control solution was added to each well.
• Hoechst 33342 solution diluted with Dulbecco's phosphate buffer (D-PBS) was added to each well.
• D-PBS Dulbecco's phosphate buffer
• Staining was performed. After staining, the cells were fixed in 4% paraformaldehyde for 20 minutes in a 37 ° C. CO 2 incubator.
• Toxinsight was used to count the number of fluoresced nuclei per well.
• the compound exposure concentration (IC 50 ) at which the mean value decreases by 50% or more from the mean value of the negative control is calculated as compared to the negative control group. The smaller the IC 50 value, the higher the risk of cytotoxicity.
• Test Example 7 O-deethylation of 7-ethoxyresorufin (CYP1A2), methyl tolbutamide as a typical substrate metabolic reaction of human major CYP5 species (CYP1A2, 2C9, 2C19, 2D6, 3A4) using commercially available pooled human liver microsomes
• the amount of each metabolite is calculated by using -hydroxylation (CYP2C9), 4'-hydroxylation of mephenytoin (CYP2C19), O demethylation of dextromethorphan (CYP2D6), and hydroxylation of terfenadine (CYP3A4) as indexes.
• the degree of inhibition by the compounds of the invention was evaluated.
• reaction conditions are as follows: substrate, 0.5 ⁇ mol / L ethoxyresorufin (CYP1A2), 100 ⁇ mol / L tolbutamide (CYP2C9), 50 ⁇ mol / L S-mephenytoin (CYP2C19), 5 ⁇ mol / L dextromethorphan (CYP2D6), Reaction time, 15 minutes; reaction temperature, 37 ° C .; enzyme, pooled human liver microsome 0.2 mg protein / mL; compound concentration of the present invention: 1, 5, 10, 20 ⁇ mol / L (4 points) .
• resorufin CYP1A2 metabolite
• LC / MS / MS fluorescent multilabel counter
• CYP2C9 metabolite mephenytoin 4 'hydroxylate
• CYP3A4 metabolite terfenadine alcohol
• a control (100%) was prepared by adding only DMSO, which is a solvent in which the drug was dissolved, as a control (100%), the residual activity (%) was calculated, and IC 50 was calculated by inverse estimation using a logistic model using concentration and inhibition rate. Calculated. (result) Compound II-103: 5 species> 20 ⁇ mol / L
• Intravenous administration was performed from the tail vein or the femoral vein by a syringe with a needle.
• Test Example 9 CYP3A4 (MDZ) MBI Test
• MBI mechanism based inhibition
• reaction conditions are as follows: substrate, 10 ⁇ mol / L MDZ; pre-reaction time, 0 or 30 minutes; reaction time, 2 minutes; reaction temperature, 37 ° C .; pooled human liver microsomes, 0.5 mg / mL at pre-reaction time, 0.05 mg / mL (at 10-fold dilution); concentration at the time of pre-reaction of the compound of the present invention, 1, 5, 10, 20 ⁇ mol / L (4 points).
• a control (100%) is obtained by adding only DMSO, which is a solvent in which the compound of the present invention is dissolved, to the reaction system, and the remaining activity (%) when each concentration of the compound of the present invention is added is calculated.
• IC was calculated by inverse estimation with a logistic model using. IC of the Preincubataion 0 min / IC of the Preincubataion 30 min was set as the Shifted IC value, and if the Shifted IC was 1.5 or more, it was regarded as Positive, and if the Shifted IC was 1.0 or less, it was regarded as Negative. (result) Compound II-103: Negative
• Test Example 10 An appropriate amount of the compound of the present invention is placed in a suitable container, and JP-1 solution (sodium chloride 2.0 g, 7.0 mL of hydrochloric acid and water is added to make 1000 mL), JP-2 solution (phosphoric acid of pH 6.8) is added to each container 200 mL of each of 500 mL of a salt buffer solution and 500 mmol of water), 20 mmol / L sodium taurocholate (TCA) / JP-2 solution (JPA 2 solution is added to 1.08 g of TCA to make 100 mL) were added. When the entire solution was dissolved after addition of the test solution, the compound of the present invention was appropriately added.
• JP-1 solution sodium chloride 2.0 g, 7.0 mL of hydrochloric acid and water is added to make 1000 mL
• JP-2 solution phosphoric acid of pH 6.8
• TCA sodium taurocholate
• JPA 2 solution is added to 1.08 g of TCA to make 100 mL
• Test example 11 Fluctuation Ames test
• S. typhimurium S. typhimurium strain TA98 strain, strain TA100
• 10 mL liquid nutrient medium (2.5% Oxoid nutrient broth No. 2)
• the TA98 strain was subjected to centrifugation (2000 ⁇ g, 10 minutes) to remove the culture solution by centrifugation of 8.0 mL of the bacterial solution.
• Micro F buffer K 2 HPO 4 : 3.5 g / L, KH 2 PO 4 : 1 g / L, (NH 4 ) 2 SO 4 : 1 g / L, trisodium citrate dihydrate: 0.25g / L, MgSO 4 ⁇ 7H 2 0: 0.1g / L
• Exposure number media 120 mL (biotin: 8 [mu] g / mL, histidine: 0.2 [mu] g / mL, glucose: an 8 mg / mL (In MicroF buffer).
• the TA100 strain was added to 120 mL of Exposure medium with respect to 3.1 mL of bacterial solution to prepare a test bacterial solution.
• the compound of the present invention DMSO solution (maximum dose 50 mg / mL to a few dilutions by 2-3 fold common ratio), DMSO as a negative control, 50 ⁇ g / mL Nitroquinoline-1-oxide DMSO solution, 0.25 ⁇ g / mL 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution for strain TA100, TA98 for metabolic activation conditions 12 ⁇ L each of 40 ⁇ g / mL 2-aminoanthracene DMSO solution for the strain and 20 ⁇ g / mL 2-aminoanthracene DMSO solution for the TA 100 strain (588 ⁇ L of the test solution under metabolic activation conditions and S98 of S9 solution) mix (90 ⁇ L of mixture) was mixed and shake cultured at
• Test example 12 Delayed rectification plays an important role in ventricular repolarization process using CHO cells expressing human ether-a-go-go related gene (hERG) channel for the purpose of risk evaluation of ECG QT interval prolongation of the compound of the present invention
• I Kr K + current
• Cells are kept at a membrane potential of -80 mV by whole cell patch clamp method using a fully automatic patch clamp system (QPatch; Sophion Bioscience A / S), and after applying a leak potential of -50 mV, +20 mV depolarization stimulation For 2 seconds, and an additional ⁇ 50 mV repolarization stimulus for 2 seconds was used to record I Kr induced.
• the compounds of the present invention may be administered by any conventional route, in particular enterally, for example orally, for example in the form of tablets or capsules, or parenterally, for example in the form of injection solutions or suspensions. It can be administered topically, for example, in the form of lotions, gels, ointments or creams, or as a pharmaceutical composition in nasal or suppository form.
• Pharmaceutical compositions comprising the compounds of the present invention in free form or in the form of a pharmaceutically acceptable salt, combined with at least one pharmaceutically acceptable carrier or diluent, are mixed in a conventional manner, It can be produced by granulation or coating methods.
• the composition for oral use can be a tablet, a granule, or a capsule containing an excipient, a disintegrant, a binder, a lubricant, and the like and an active ingredient and the like.
• the composition for injection may be a solution or suspension, may be sterilized, and may contain a preservative, a stabilizer, a buffer, and the like.
• MGAT2 such as obesity, metabolic syndrome, hyperlipidemia, hypertriglyceridemia, hyperVLDLemia, hyperlipidemia, diabetes, arteriosclerosis and the like It is useful as a medicine for the diseases involved.

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