WO2014169817A1 - Composé de phénylalanine ayant un groupe de liaison hétérocyclique azoté, composition pharmaceutique associée, son procédé de préparation et son utilisation - Google Patents

Composé de phénylalanine ayant un groupe de liaison hétérocyclique azoté, composition pharmaceutique associée, son procédé de préparation et son utilisation Download PDF

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WO2014169817A1
WO2014169817A1 PCT/CN2014/075466 CN2014075466W WO2014169817A1 WO 2014169817 A1 WO2014169817 A1 WO 2014169817A1 CN 2014075466 W CN2014075466 W CN 2014075466W WO 2014169817 A1 WO2014169817 A1 WO 2014169817A1
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compound
alkyl
acid
oxy
phenyl
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Chinese (zh)
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胡有洪
冷颖
李德文
宁萌萌
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中国科学院上海药物研究所
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to the field of pharmacy, and in particular to a phenylpropionic acid compound containing a nitrogen-containing heterocyclic link, and a medicament thereof a physiologically acceptable salt, stereoisomer or prodrug molecule thereof, pharmaceutical composition thereof, preparation method, and use thereof in the preparation of a medicament for treating diabetes and disorders of glycolipid metabolism, especially in the preparation of type II diabetes Use of the drug.
  • the above compounds have a remarkable function of lowering blood sugar and regulating glycolipid metabolism activity.
  • Background Art It is well known that diabetes is a chronic disease that is the third most serious threat to human health after cancer and cardiovascular and cerebrovascular diseases.
  • Type I diabetes is characterized by a lack of insulin secretion called insulin-dependent diabetes mellitus (IDDM), which is caused by its inability to use insulin effectively, called non-insulin-dependent diabetes mellitus (NIDDM).
  • IDDM insulin-dependent diabetes mellitus
  • NIDDM non-insulin-dependent diabetes mellitus
  • Type II diabetes accounts for more than 90% of the global diabetes population.
  • the pathogenesis of type 2 diabetes mellitus is complicated, and its basic characteristics are that skeletal muscle, liver, fat and other tissues are resistant to insulin.
  • islet ⁇ cells can compensate insulin secretion to compensate for the deficiency of insulin, thus maintaining normal blood sugar levels.
  • the islet ⁇ -cell insulin secretion function is insufficient, and the patient's compensatory mechanism collapses, resulting in abnormally elevated blood glucose levels, which in turn leads to the formation of type 2 diabetes in the body.
  • GTP-binding protein coupling receptor 40 (GP 40) is a seven-pass transmembrane receptor. It is abundantly expressed in islets and is also expressed in the intestinal system. Current research suggests that this transmembrane receptor may be associated with certain cancers, neurological diseases, and metabolic diseases, especially diabetes. Studies have found that various forms of free fatty acid (FFA) are natural ligands for GPR40. FFA amplifies glucose-stimulated insulin secretion by activating GPR40 on the islet beta cell membrane. Given that GPR40 receptor agonists have a glucose-dependent advantage in promoting insulin secretion, they are potential targets for the treatment of diabetes.
  • FFA free fatty acid
  • the present invention is directed to compounds having the structure of Formula I below which are distinct from the structures of the reported compounds.
  • the compound of the present invention has a remarkable function of lowering blood sugar and regulating glycolipid metabolism activity, and is a novel type of GPR40 agonist.
  • An object of the present invention is to provide a phenylpropionic acid compound represented by the following formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer thereof, a racemate and a mixture thereof, or a stereoisomer thereof Body, or its prodrug molecule.
  • Another object of the present invention is to provide a process for the preparation of a phenylpropionic acid compound of the formula I.
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a phenylpropionic acid compound selected from the formula I, a pharmaceutically acceptable salt thereof, an enantiomer thereof, and the like Racemization One or more of a mixture, a mixture thereof, a stereoisomer thereof and a prodrug molecule thereof, and a pharmaceutically acceptable excipient.
  • a further object of the present invention is to provide a phenylpropionic acid compound selected from the formula I, a pharmaceutically acceptable salt thereof, an enantiomer thereof, a racemate and a mixture thereof, and stereoisomers thereof Use of one or more of a body and a prodrug molecule thereof for the manufacture of a medicament for the treatment of diabetes and disorders of glycolipid metabolism.
  • It is still another object of the present invention to provide a method of treating diabetes and disorders of glycolipid metabolism comprising administering to a subject in need of such treatment a phenylpropionic acid compound selected from Formula I or a pharmaceutically acceptable compound thereof.
  • a phenylpropionic acid compound selected from Formula I or a pharmaceutically acceptable compound thereof.
  • One aspect provides a phenylpropionic acid compound of the formula I:
  • R n R 2 are each independently selected from the group consisting of H, hydroxy, halogen, nitro, dC ⁇ fluorenyl, halo dC ⁇ fluorenyl, dC ⁇ decyloxy, halo dC ⁇ decyloxy, C 3 -C 1() a cycloalkyl group and a 3- to 10-membered heterocyclic group containing 1 to 3 hetero atoms selected from S, 0 and N; preferably selected from the group consisting of H, hydroxy, halogen, nitro, CC 6 ⁇ ⁇ CrC 6 C ⁇ - C 6 3 ⁇ 43 ⁇ 4 , ⁇ ⁇ CC 6 C 3 -C 8 i groups and 3 to 10 membered heterocyclic groups containing at least one nitrogen atom; more preferably each independently selected from H, hydroxy, halogen, nitro, C r C 4 -mercapto, halo C r C 4 fluorenyl, C r C 4 decyloxy,
  • R 3 is selected from the group consisting of H; halogen; carboxy; C r C 2 () fluorenyl; halogenated C r C 2 () fluorenyl; -O a ; -N( a ) S0 2 b , -NR ab; -N ( a ) C(0) b ; -C(0)NR ab ; -S0 2 a ; -S b ; selected from C d .
  • ⁇ Preferably selected from H ; halogen; carboxy; C r C 6 fluorenyl; halogenated C r C 6 fluorenyl; -OR a; -N( a )S0 2 b ; -NR ab; -N( a )C(0 b ; -C(0)NR ab ; -S0 2 a ; -S b ; selected from CC 4 decyloxy, C 3 -C 8 cyclodecyl, -SR C , -S0 2 R c , -NR Cd or substituted C substituted by a substituent in a 3-6 membered heterocyclic group containing 1 to 3 heteroatoms selected from 0, S and N substituted by dC 4 fluorenyl, hydroxy or oxo group r C 6 embankment group; and the embankment with a C r C 4 group, 3 - 8 cycloalkyl group embankment, -SR
  • R b are each independently selected from the group consisting of H, C r C 6 fluorenyl, C 3 -C 8 cyclodecyl and unsubstituted or substituted by C r C 6 fluorenyl or oxo group and selected from 0, S and N 3-8 membered heterocyclic groups of 1 to 3 heteroatoms; preferably each independently selected from H, C r C 4 fluorenyl, C 3 -C 6 cyclodecyl and unsubstituted or C r C 3 fluorenyl Or a methoxy group-substituted 3-6 membered heterocyclic group containing 1 to 3 heteroatoms selected from the group consisting of 0, S and N;
  • R c and R d are each independently selected from H, C r C 6 fluorenyl and 3- substituted or substituted by ( ⁇ - 3 fluorenyl) containing 1 to 3 heteroatoms selected from 0, S and N 8-membered heterocyclic group; preferably each independently selected from H, C r C 3 fluorenyl and unsubstituted or substituted by C r C 3 fluorenyl containing 1 to 3 heteroatoms selected from 0, S and N 3-6 membered heterocyclic group;
  • R 4 is selected from the group consisting of H, hydroxy, halogen, dC fluorenyl and halogenated dC fluorenyl; preferably H, hydroxy, halogen, C r C 6 fluorenyl and halogenated C r C 6 fluorenyl,
  • R 5 is selected from the group consisting of H, halogen and dC fluorenyl; preferably H, halogen and C r C 6 fluorenyl; or R 4 together with the carbon atom attached thereto and benzene ring together form a benzo 5-8 membered heterocyclic ring group, containing heterocycle selected from 0, N and S, 1 to 3 hetero atoms, and said heterocyclic group is unsubstituted or substituted alkyl with C r C 6; R 4 and preferably together with it, and The linked carbon atom together with the benzene ring form a benzo 5-membered heterocyclic group containing one to two heteroatoms selected from the group consisting of 0, N and S. And not substituted or substituted by C r C 3 thiol; further preferably, R 4 and associated with it
  • Carbon atoms form together with the benzene ring or.
  • phenylpropionic acid compound of the formula I of the present invention has a structure represented by the following formula II or formula III:
  • R 6 is H or C r C 6 fluorenyl, and in Formula III, when Z is 0 or S, R 6 is absent.
  • halogen includes fluorine, chlorine, bromine and iodine.
  • halo refers to a single or multiple halogen atoms selected from the group consisting of fluorine, chlorine, bromine and iodine.
  • d-o fluorenyl refers to a straight or branched fluorenyl group having from 1 to 20 carbon atoms in the main chain, and includes, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl Base, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, octyl, decyl, undecyl, fluorenyl, tetradecyl, sixteenth, seventeen , 18 courtyards, 20 courtyards, etc.
  • C C6 yard base and "Ci-Gt yard base” have similar meanings.
  • d-omethoxy refers to a straight or branched decyloxy group having from 1 to 20 carbon atoms in the main chain, and includes, without limitation, methoxy, ethoxy, n-propoxy, and iso Propyloxy, butoxy, pentyloxy, hexyloxy, octyloxy, decyloxy, undecyloxy, dodecyloxy, tetradecyloxy, hexadecanyloxy, seventeen Oxygen, ten hospital oxygen, twenty hospital oxygen, etc.
  • CK "Ci-C 6 methoxy" and "C r C 4 methoxy” have similar meanings.
  • C 3 -C 1 () cyclodecyl refers to a cyclic fluorenyl group having 3 to 10 carbon atoms in the ring, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. And cycloheptyl; the terms “C 3 -C 8 cyclodecyl” and “C 3 -C 6 cyclodecyl” have similar meanings.
  • 3-8 membered heterocyclic group means a non-aromatic ring group having 3-8 atoms on the ring containing at least one atom selected from the group consisting of N, 0 and S atoms, such as an epoxy group, a pyrrolidinyl group, Morpholinyl and the like; the terms “5-8 membered heterocyclic group” and “3-6 membered heterocyclic group” have similar meanings.
  • pharmaceutically acceptable salt in the present invention means a compound represented by the formula I according to the present invention and a mineral acid such as phosphoric acid, sulfuric acid or hydrochloric acid, or acetic acid, tartaric acid, citric acid, malic acid or fumaric acid.
  • An organic acid, or a salt formed by an acidic amino acid such as aspartic acid or glutamic acid, or a salt formed with an inorganic base after forming an ester or an amide with the above-mentioned acid, such as sodium, potassium, calcium, aluminum salt and ammonium salt.
  • the compound is preferably selected from the following compounds:
  • Step 1 R 4 -substituted p-bromobenzyl alcohol 1 and ethyl acrylate 2 are subjected to Heck reaction to obtain intermediate 3, and the double bond is reduced to obtain intermediate 4, and then bromination is carried out to convert benzyl alcohol into benzyl bromide to obtain intermediate
  • the Heck reaction can be carried out, for example, in the presence of a palladium metal catalyst such as palladium acetate, tetrakis(triphenylphosphine)palladium or bis(triphenylphosphine)palladium dichloride, for example, ruthenium, osmium-dimethylformamide.
  • the double bond reduction reaction can be carried out using, for example, hydrogen gas in a solvent such as ethyl acetate, butyl acetate, methanol, ethanol or n-propanol in the presence of, for example, a palladium carbon composite catalyst.
  • the bromination reaction can be carried out using a brominating agent such as phosphorus tribromide, phosphorus pentabromide, phosphorus oxybromide or dibromosulfoxide in a solvent such as acetonitrile, dichloromethane or diethyl ether;
  • Step 2 Intermediate 5 and substrate 6 are subjected to nucleophilic substitution reaction to obtain intermediate 7;
  • the nucleophilic substitution reaction can be, for example, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, potassium t-butoxide, tert-butyl
  • a base such as sodium acetate or sodium hydroxide
  • a solvent such as acetonitrile, hydrazine, hydrazine-dimethylformamide or tetrahydrofuran;
  • Step 3 Intermediate 7 and The intermediate 8 is obtained by Suzuki reaction coupling, and the intermediate 8 is subjected to hydrolysis reaction to obtain the product 9;
  • the Suzuki reaction may be, for example, a mixed solvent of toluene/acetonitrile/water in the presence of a catalyst such as tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, palladium acetate or palladium carbon composite, a mixed solvent of toluene/ethanol/water, a mixed solvent of acetonitrile/water or a mixed solvent of ethanol/water; and the hydrolysis reaction of the intermediate 8 may be a base such as potassium hydroxide, sodium hydroxide or lithium hydroxide.
  • a solvent such as an acetonitrile/water mixed solvent, a methanol/water mixed solvent or an ethanol/water mixed solvent;
  • Step 1 Compound 17 (wherein Z is 0 or S, R 6 is absent) or 20 (wherein Z is N, R 6 is H or C r C 6 fluorenyl) and substrate 6 is subjected to nucleophilic substitution reaction
  • Compound 21 is obtained, and the nucleophilic substitution reaction can be carried out, for example, in the presence of a catalyst such as potassium carbonate, cesium carbonate, sodium hydride, potassium t-butoxide or sodium t-butoxide in, for example, acetonitrile, acetone, ethyl acetate, tetrahydrofuran or hydrazine.
  • a catalyst such as potassium carbonate, cesium carbonate, sodium hydride, potassium t-butoxide or sodium t-butoxide in, for example, acetonitrile, acetone, ethyl acetate, tetrahydrofuran or hydrazine.
  • a catalyst such as potassium carbonate, cesium carbonate, sodium
  • Step 2 Compound 21 and The intermediate 22 is obtained by Suzuki reaction coupling, and the intermediate 22 is subjected to hydrolysis reaction to obtain the product 23;
  • the Suzuki reaction can be, for example, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride,
  • a catalyst such as palladium acetate or palladium carbon composite
  • a mixed solvent such as toluene/acetonitrile/water, a mixed solvent of toluene/ethanol/water, a mixed solvent of acetonitrile/water or a mixed solvent of ethanol/water
  • the hydrolysis can be carried out in the presence of a base such as potassium hydroxide, sodium hydroxide or lithium hydroxide in a solvent such as an acetonitrile/water mixed solvent, a methanol/water mixed solvent or an ethanol/water mixed solvent.
  • the compounds 17 and 20 can be prepared by the following method:
  • Step 1 The hydroxyl group of the compound 10 is protected with a protective agent to obtain a compound 11, and then subjected to a Friedel-Craft reaction with chloroacetyl chloride to obtain a compound 12;
  • the protective agent may be acetic anhydride, acetyl chloride or acetyl bromide, and the reaction for protecting the hydroxyl group may be, for example, dichloro in the presence of a catalyst such as triethylamine, diisopropylethylamine or 4-dimethylaminopyridine.
  • the Friedel-Craft reaction can be, for example, in the presence of a catalyst such as aluminum trichloride, zinc dichloride or boron trifluoride diethyl ether solution; In a solvent such as dichloromethane, trichloromethane or diethyl ether;
  • Step 2 Compound 12 is subjected to intramolecular nucleophilic substitution reaction to obtain compound 13, and then subjected to a fitting reaction with a Witting reagent to obtain a compound 14;
  • the intramolecular nucleophilic substitution reaction can be, for example, sodium acetate, potassium acetate, potassium carbonate, tert-butyl
  • a base such as potassium alkoxide or sodium t-butoxide
  • a solvent such as methanol, ethanol or acetonitrile
  • the witting reaction can be carried out in a solvent such as toluene, benzene or xylene.
  • Step 3 Compound 14 is subjected to hydrogenation reduction to obtain compound 15.
  • compound 15 is hydrolyzed to obtain compound 16, and compound 16 is subjected to bromination reaction, followed by dropwise addition.
  • Anhydrous ethanol is subjected to an esterification reaction to obtain a compound 17;
  • the reduction reaction can be carried out in the presence of a catalyst such as palladium on carbon in a solvent such as methanol, ethanol or ethyl acetate;
  • the hydrolysis reaction can be, for example, sodium hydroxide or hydrogen
  • the bromination reaction may be, for example, phosphorus tribromide, phosphorus pentabromide, phosphorus oxybromide Or in the presence of a brominating agent such as dibromosulfoxide in a solvent such as acetonitrile or ethyl acetate;
  • the bromination reaction may be, for example, phosphorus tribromide, phosphorus pentabromide, phosphorus oxybromide or dibromosulfoxide.
  • a brominating agent in a solvent such as acetonitrile or ethyl acetate;
  • ⁇ is 0, S or N, and R 7 is C r C 6 fluorenyl
  • a pharmaceutical composition comprising a therapeutically effective amount of a phenylpropionic acid compound selected from the above formula I, an enantiomer thereof, a racemate thereof And one or more of a mixture thereof and a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.
  • the pharmaceutical composition can be used to treat diabetes or disorders of glycolipid metabolism.
  • a further aspect of the invention provides a phenylpropionic acid compound selected from the formula I, an enantiomer thereof, a racemate, and mixtures thereof, stereoisomers thereof, prodrug molecules thereof, and Use of one or more of the pharmaceutically acceptable salts for the manufacture of a medicament for the treatment of diabetes or disorders of glycolipid metabolism.
  • a method of treating diabetes or a disorder of glycolipid metabolism comprising administering to a patient in need thereof a therapeutically effective amount of a phenylpropionic acid compound selected from the present invention, which is aligned One or more of the isomers, racemates and mixtures thereof, stereoisomers thereof, prodrug molecules thereof, and pharmaceutically acceptable salts thereof, or a pharmaceutical composition according to the present invention.
  • the nuclear magnetic resonance spectrum was recorded with a Bmker AMX-400, Gemini-300 or AMX-600 nuclear magnetic resonance instrument, and the unit of chemical shift ⁇ was ppm.
  • the specific optical rotation was measured by a Perkin-Elmer Model 241, and the microwave used was a CEM-discovery microwave reactor. All reaction solvents were purified according to a conventional method. Column chromatography with silica gel (200-300 mesh) is produced by Qingdao Ocean Chemical Branch. Thin layer chromatography was performed using the GF254 high efficiency plate for the Yantai Institute of Chemical Industry. Preparative thin-layer chromatography plates were prepared by themselves.
  • the stationary phase was prepared by GF254 (HG/T2354-92) silica gel and sodium carboxymethylcellulose (800-1200), respectively, Qingdao Ocean Chemical Co., Ltd. and China Pharmaceutical (Group). Shanghai Chemical Reagent Company produces. All solvents were analytically pure reagents, and the reagents used were purchased from Sinopharm Chemical Reagent Co., Ltd. Color development was carried out by means of iodine or ultraviolet fluorescence. The organic solvent was distilled off under reduced pressure in a rotary evaporator.
  • the compound 3-(4-((6-(2-methylphenyl)pyridin-2-yl)) was prepared in a similar manner to Example 4 except that 2-methylphenylboronic acid was used instead of phenylboronic acid. Oxygen)methylene)phenyl)propionic acid.
  • the compound 3-(4-((6-(4-methylphenyl)pyridin-2-yl)oxy) was prepared in a similar manner to Example 4 except that p-methylbenzeneboronic acid was used instead of phenylboronic acid. Methylene)phenyl)propionic acid.
  • the compound 3-(4-((6-(2-ethylphenyl)pyridin-2-yl)oxy) was prepared in a similar manner to Example 4 except that 2-ethylbenzeneboronic acid was used instead of phenylboronic acid. Methylene)phenyl)propionic acid.
  • the compound 3-(4-((6-(2-isopropylphenyl)pyridin-2-yl) was prepared in a similar manner to Example 4 except that 2-isopropylbenzeneboronic acid was used instead of phenylboronic acid. Oxy)methylene)phenyl)propionic acid.
  • the compound 3-(4-((6-(2-tert-butylphenyl)pyridin-2-yl) was prepared in a similar manner to Example 4 except that 2-isobutylbenzeneboronic acid was used instead of phenylboronic acid. Oxy)methylene)phenyl)propionic acid.
  • the compound 3-(4-((6-(2-nitrophenyl)pyridin-2-yl) was prepared in a similar manner to that shown in Example 4 except that 2-nitrophenylboronic acid was used instead of phenylboronic acid. Oxy)methylene)phenyl)propionic acid.
  • the compound 3-(4-((6-(2-hydroxyphenyl)pyridin-2-yl)oxy)) was prepared in a similar manner to Example 4 except that 2-hydroxyphenylboronic acid was used instead of phenylboronic acid. Methyl)phenyl)propionic acid.
  • the compound 3-(4-((6-(2-(trifluoromethyl)phenyl)pyridine) was prepared in a similar manner to Example 4 except that 2-trifluoromethylbenzeneboronic acid was used instead of phenylboronic acid. -2-yl)oxy)methylene)phenyl)propanoic acid.
  • the compound 3-(4-((6-(2-methoxyphenyl)pyridin-2-yl) was prepared in a similar manner to Example 4 except that 2-methoxyphenylboronic acid was used instead of phenylboronic acid. Oxy)methylene)phenyl)propionic acid.
  • the compound 3-(4-((6-(2-methylaminophenyl)pyridin-2-yl)) was prepared in a similar manner to Example 4 except that 2-methylaminobenzeneboronic acid was used instead of phenylboronic acid. Oxygen)methylene)phenyl)propionic acid.
  • the compound 3-(4-((6-(2,6-diethylphenyl)pyridine) was prepared in a similar manner to Example 4 except that 2,6-diethylbenzeneboronic acid was used instead of phenylboronic acid. -2-yl)oxy)methylene)phenyl)propanoic acid.
  • the compound 3-(4-((6-(2,6-dimethoxyphenyl)) was prepared in a similar manner to Example 4 except that 2,6-dimethoxyphenylboronic acid was used instead of phenylboronic acid. Pyridin-2-yl)oxy)methylene)phenyl)propanoic acid.
  • the compound 3-(4-((6-(2,6-difluorophenyl)pyridine-2) was prepared in a similar manner to Example 4 except that 2,6-difluorophenylboronic acid was used instead of phenylboronic acid. -yl)oxy)methylene)phenyl)propanoic acid.
  • the compound 3-(4-((6-(2,6-methyl-)-) was prepared in a similar manner to Example 4 except that 2,6-dimethyl-4-hydroxybenzeneboronic acid was used instead of phenylboronic acid. 4-Hydroxyphenyl)pyridinyloxy)methylene)phenyl)propanoic acid.
  • the compound 3-(4-((6-(2,4,6-trimethyl)) was prepared in a similar manner to Example 4 except that 2,4,6-trimethylphenylboronic acid was used instead of phenylboronic acid. Phenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid.
  • the compound 3-(4-((6-(4-amino-2,6)) was obtained in a similar manner to Example 4 except that 2,6-dimethyl-4-aminophenylboronic acid was used instead of phenylboronic acid. -Dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propionic acid.
  • the compound 3-(4-((6-(4-carboxy-2,6)) was obtained in a similar manner to Example 4 except that 2,6-dimethyl-4-carboxylic acid phenylboronic acid was used instead of phenylboronic acid. -Dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propionic acid.
  • the compound 3-(4-((6-(4-amido)-) was prepared in a similar manner to Example 4 except that 2,6-dimethyl-4-carbamoylbenzeneboronic acid was used instead of phenylboronic acid. 2,6-Dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid.
  • the compound 3-(4-((6-(4-fluoro-2,6)) was prepared in a similar manner to Example 4 except that 2,6-dimethyl-4-fluorobenzeneboronic acid was used instead of phenylboronic acid.
  • 2,6-dimethyl-4-fluorobenzeneboronic acid was used instead of phenylboronic acid.
  • the compound 3-(4-((6-(4-methoxy)) was prepared in a similar manner to Example 4 except that 2,6-dimethyl-4-methoxyphenylboronic acid was used instead of phenylboronic acid.
  • 2,6-dimethyl-4-methoxyphenylboronic acid was used instead of phenylboronic acid.
  • -2,6-Dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid was prepared in a similar manner to Example 4 except that 2,6-dimethyl-4-methoxyphenylboronic acid was used instead of phenylboronic acid.
  • a compound 3-K 6-(4-methylthio-2,6- was obtained in a similar manner to Example 4 except that 2,6-dimethyl-4-methylmercaptophenylboronic acid was used instead of phenylboronic acid.
  • a compound 3-(4-:(:6-(2,6-dimethyl) was obtained in a similar manner to Example 4 except that 2,6-dimethyl-4-methylaminobenzeneboronic acid was used instead of phenylboronic acid.
  • a compound 3-(4-:(6-(2,) was obtained in a similar manner to Example 4 except that 2,6-dimethyl-4-(dimethylamino:)benzeneboronic acid was used instead of phenylboronic acid. 6-Dimethyl-4-dimethylaminophenyl:)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid.
  • a compound 3-(4-:(:6) was obtained in a similar manner to Example 4 except that 2,6-dimethyl-4-(methylsulfonylmethyl:)aminobenzeneboronic acid was used instead of phenylboronic acid.
  • 2,6-dimethyl-4-(methylsulfonylmethyl:)aminobenzeneboronic acid was used instead of phenylboronic acid.
  • -(2,6-Dimethyl-4-(N-methylmethanesulfonamide)phenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid was used instead of phenylboronic acid.
  • Example 38 3-(4-((6-(2,6-Dimethylphenyl)pyridin-2-yl)oxy)methylene)-2-chlorophenyl)propanoic acid (Compound HYH- 035)
  • Example 40 3 -( 4 -(( 6- ( 2 , 6 -Dimethyl- 4 -hydroxyphenyl)pyridine- 2 -yl)oxy)methylene) -2 -chlorophenyl)propanoic acid (Compound HYH-037
  • the 85 mg sample obtained above was dissolved in a mixture of 8 mL of acetonitrile and 2 mL of water, and 10 mg of lithium hydroxide was added thereto, and reacted at 40 ° C for 4 hours, cooled, adjusted to pH 2-3 with 1 M hydrochloric acid, and 20 mL of saturated brine was added thereto.
  • the organic layer was combined and dried over anhydrous sodium sulfate and filtered to give 3-(4-(2, 6-dimethyl-4-(2-(methylsulfonyl)) 68 mg of ethoxy)phenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid as a white solid, yield 84%.
  • Example 42 3-(4-((6-(2,6-Dimethyl-4-(2-(ethanesulfonyl)ethoxy)phenyl)pyridin-2-yl)oxy)) Preparation of phenyl)propionic acid (compound HYH-039)
  • the compound 3-(4-(:6-) was obtained in a similar manner to Example 41 except that 2-ethylsulfonylethyl p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester.
  • a compound 3-(4-:(:6) was obtained in a similar manner to Example 41 except that 3-methanesulfonylpropyl p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester.
  • the compound 3-(4-:(:6) was obtained in a similar manner to Example 41 except that 3-ethylsulfonylpropyl p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester.
  • 3-ethylsulfonylpropyl p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester.
  • -(2,6-Dimethyl-4-(3-(ethylsulfonyl)propoxy)phenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester.
  • a compound 3-K was prepared in a similar manner to Example 41 except that 2-methoxyethyl-p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester.
  • a compound 3-(4-: was obtained in a similar manner to that shown in Example 41 except that 2-ethoxyethyl p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. : 6-(4-(2-ethoxyethoxy)-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid.
  • Compound 3-(4-) was prepared in a similar manner to Example 42 except that 2-dimethyl:) amino: ethyl p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. (((6-(4-(2-Dimethylaminoethoxy)-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid.
  • a compound 3-(4-X6) was obtained in a similar manner to Example 41 except that 3-(diethylamino)propyl p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester.
  • 3-(diethylamino)propyl p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester.
  • -(4-p-Diethylaminopropoxy)-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester.
  • Example 41 A method similar to that of Example 41 was used except that 1,1-dioxotetrahydro-2/7-thiopyran-4-p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester.
  • the compound 3-K 6-(2,6- was obtained in a similar manner to Example 41 except that 2-morpholine ethyl p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. Dimethyl-4-(2-morpholineethoxy)phenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid.
  • Step 2 Dissolve 9.7 g of 3-methoxybenzyl alcohol acetate in 40 mL of anhydrous dichloromethane, add 12.8 mL of chloroacetyl chloride dropwise at room temperature, and then add 23.6 g of anhydrous chlorinated in multiple batches. Aluminum was then refluxed for 16 hours.
  • Step 5 Dissolve 1.15 g of 6-hydroxymethyl acetate-benzofuran-3-yl:ethyl acetate into 20 mL of ethyl acetate, add 10% Pd/C 100 mg, hydrogen at atmospheric pressure The atmosphere was allowed to stand overnight at room temperature, and the diatomaceous earth was passed over to remove palladium carbon, and the filtrate was concentrated and separated on a silica gel column to obtain ethyl (6-hydroxymethyl acetate-2,3-dihydrobenzofuran-3-yl)acetate.
  • Step 6 Dissolve 6. Og of 6-hydroxymethyl acetate-2,3-dihydrobenzofuran-3-yl:)acetate in 20 mL of acetonitrile, add 4 mL of water, and add 100 mg of hydrogen with stirring. Lithium oxide was reacted at 50 ° C for 4 hours, cooled to room temperature, 50 mL of water was added, and extracted with dichloromethane for 3 times. The combined organic layers were dried over anhydrous sodium sulfate to give (6-hydroxymethyl-2,3- 0.68 g of dihydrobenzofuran-3-yl)acetic acid was an off-white solid with a yield of 91%.
  • Step 7 0.65 g of (6-hydroxymethyl-2,3-dihydrobenzofuran-3-yl)acetic acid was added to a 10 mL round bottom flask, and 1 mL of phosphorus tribromide was added dropwise, and the reaction was carried out at 80 ° C. After 2 hours, the reaction solution was cooled to 0 ° C, and 1.0 mL of anhydrous ethanol was added dropwise, and the reaction mixture was poured into 100 mL of ice water, and the mixture was extracted three times with ethyl acetate.
  • Step 1 0.5 g of (6-hydroxymethyl-2,3-dihydrobenzofuran-3-yl)acetate and 0.29 g of 2-bromo-6-hydroxypyridine were dissolved in 20 mL of acetonitrile, and added to 0.35. g potassium carbonate, then reacted at 60 ° C for 3 hours, cooled to room temperature, and concentrated on a column to give 2-(6-((6-bromopyridin-2-yl)oxy)methylene)-2,3 Ethyl dihydrobenzofuran-3-yl)acetate 0.58 g, yield 88%.
  • Step 2 Weigh 100.Omg of compound 2-(6-((6-bromopyridin-2-yl)oxy)methylene)-2,3-dihydrobenzofuran-3-yl)acetic acid Ester, 65.0 mg 4-hydroxy-2,6-dimethylphenylboronic acid, 15.0 mg of tetrakis(triphenylphosphine)palladium and 75.0 mg of potassium carbonate were added to a 10 mL microwave reactor special tube, and 2.0 mL of toluene, 0.4 mL was added. Ethanol and 0.4 mL of water were replaced with nitrogen for 3 times, and then placed in a CEM microwave reactor at 120 ° C for 30 minutes.
  • Step 3 and Step 4 In addition to using 2-(6-((6-(4-hydroxy-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene)-2, 3-(4-((6-(2,6-dimethyl-4-hydroxyphenyl)pyridin-2-yl)oxy)) In the same manner as in Example 42 except that methyl (ethyl)phenyl)propanoate was obtained, 2-(6-((6-(2,6-dimethyl-4-(2-) Methanesulfonyl)ethoxy)phenyl)pyridin-2-yl)oxy)methylene)-2,3-dihydrobenzofuran-3-yl)acetic acid.
  • Example 67 2-(6-((6-(2,6-Dimethyl-4-(4-(methylsulfonyl)butoxy)phenyl)pyridin-2-yl)oxy)) Preparation of bis(2,3-dihydrobenzofurazol-3-yl)acetic acid (compound HYH-063)
  • Compound 2-(6-:(:6) was obtained in a similar manner to Example 65 except that 4-methanesulfonylbutyl p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester.
  • Example 69 2-(6-((6-(2,6-Dimethyl-4-(2-methoxyethoxy)phenyl)pyridin-2-yl)oxy)methylene) Preparation of -2,3-dihydrobenzofuran-3-yl)acetic acid (compound HYH-065)
  • Compound 2-(6-X6-(2) was obtained in a similar manner to Example 65 except that 2-methoxyethyl-p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester.
  • Example 70 2-(6-((6-(2,6-Dimethyl-4-(3-methoxypropoxy)phenyl)pyridin-2-yl)oxy)methylene) Preparation of -2,3-dihydrobenzofurazol-3-yl)acetic acid (compound HYH-066)
  • Compound 2-(6-X6-(2) was obtained in a similar manner to Example 65 except that 3-methoxypropyl-p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. ,6-Dimethyl-4-P-methoxypropoxy)phenyl)pyridin-2-yl)oxy)methylene)-2,3-dihydrobenzofuran-3-yl)acetic acid.
  • Example 71 2-(6-((6-(2,6-Dimethyl-4-(2-dimethylaminoethoxy)phenyl)pyridin-2-yl)oxy)methylene) Preparation of -2,3-dihydrobenzofurazol-3-yl)acetic acid (compound HYH-067)
  • a compound 2-(6-(:6-) was obtained in a similar manner to Example 65 except that 2-dimethylaminoethyl-p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester.
  • Compound 2-(6-(:6-) was obtained in a similar manner to Example 65 except that 3-dimethylaminopropyl-p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. (2,6-Dimethyl-4-P-dimethylaminopropoxy)phenyl)pyridin-2-yl)oxy)methylene)-2,3-dihydrobenzofuran-3-yl) Acetic acid.
  • Example 73 2-(6-((6-(2,6-Dimethyl-4-((tetrahydro-2-pyridin-4-yl)oxy)phenyl)pyridin-2-yl)) Preparation of Oxygen) Methylene)-2,3-Dihydrobenzofurazol-3-yl)acetic Acid (Compound HYH-069)
  • Compound 2-(6- was obtained in a similar manner to Example 65 except that tetrahydro-2/7-pyran-4-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester.
  • Compound 2-(6- was prepared in a similar manner to Example 65 except that tetrahydro-2/7-thiopyran-4-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. :(:6-(2,6-Dimethyl-4tetrahydro-2/7-thiopyran-4-yl)oxy)phenyl)pyridin-2-yl)oxy)methylene)-2, 3-Dihydrobenzofuran-3-yl)acetic acid.
  • the compound 2-(6-X6-(2,6-) was obtained in a similar manner to Example 65 except that the piperidin-4-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester.
  • the compound 2-(6-X6-() was prepared in a similar manner to Example 65 except that 1-methylpiperidine-4-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. 2,6-Dimethyl-4-G-methylpiperidin-4-yl)oxy)phenyl)pyridin-2-yl)oxy)methylene)-2,3-dihydrobenzofuran- 3-yl)acetic acid.
  • Example 77 2-(6-((6-(2,6-Dimethyl-4-((1,1-dioxotetrahydro-2-thio-4-yl)oxy)benzene) Preparation of pyridin-2-yl)oxy)methylene)-2,3-dihydrobenzofuran-3-yl)acetic acid (compound HYH-073)
  • Example 65 A method similar to that of Example 65 was carried out except that 1,1-dioxotetrahydro-2/7-thiopyran-4-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester.
  • Example 78 2-(6-((6-(4-(4-hydroxy-1,1-dioxotetrahydro-2H-thyl-4-yl)methoxy)-2,6 -Dimethylphenyl)pyridin-2-yl)oxy)methylene)-2,3-dihydrobenzofuran-3-yl)acetic acid (compound HYH-074)
  • Example 80 2-(6-((6-(2,6-Dimethyl-4-(2-(piperidin-1-yl)ethoxy)phenyl)pyridin-2-yl)oxy Preparation of methylene)-2,3-dihydrobenzofurazol-3-yl)acetic acid (compound HYH-076)
  • Compound 2-(6- was prepared in a similar manner to Example 65 except that 2-(piperidin-1-yl)ethyltoluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. :(:6-(2,6-Dimethyl-4-(2-(piperidin-1-yl)ethoxy)phenyl)pyridin-2-yl)oxy)methylene)-2,3 -Dihydrobenzofuran-3-yl)acetic acid.
  • Compound 2-(6- was prepared in a similar manner to Example 65 except that 2-(piperazin-1-yl)ethyltoluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. :(:6-(2,6-Dimethyl-4-(2-(piperazin-1-yl)ethoxy)phenyl)pyridin-2-yl)oxy)methylene)-2,3 -Dihydrobenzofuran-3-yl)acetic acid.
  • a compound was prepared in a similar manner to Example 65 except that 2-(4-methylpiperazin-1-yl:)ethyltoluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester.
  • Step 1 The compound 2-(6-(bromomethyl)-2,3- was obtained in a similar manner to Example 64 except that 3-methylthiobenzyl alcohol was used instead of 3-methoxybenzyl alcohol. Ethyl dihydrobenzothiophen-3-yl).
  • Step 2 In addition to 2-(6-(bromomethyl)-2,3-dihydrobenzothiophen-3-yl)acetate, 2-(6-(bromomethyl)-2,3- In the same manner as in Example 65, the compound 2-(6-(2-(2,6-dimethyl-4-(2)) - (Methanesulfonyl)ethoxy)phenyl)pyridin-2-yl)oxy)methylene)-2,3-dihydrobenzothiophen-3-yl)acetic acid.
  • a compound 2-(6-:(:6) was obtained in a similar manner to Example 84 except that 3-methanesulfonylpropyl p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester.
  • a compound 2-(6-:(:6) was obtained in a similar manner to Example 84 except that 4-methanesulfonylbutyl p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester.
  • 4-methanesulfonylbutyl p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester.
  • the compound 2-(6-X6-K2- was obtained in a similar manner to Example 84 except that 2-dimethylaminoethyl-p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester.
  • the compound 2-(6-X6-K3- was obtained in a similar manner to Example 84 except that 3-dimethylaminopropyl-p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester.
  • Example 90 Screening of compounds for agonistic activity of HEK293 cell line stably transfected with human GPR40
  • HEK293 cells were transfected into eukaryotic expression vector human GPR40-pCDNA3.1, and a monoclonal cell strain stably expressing human GPR40 was obtained by screening.
  • the HEK293 cell line stably transfected with human GPR40 was cultured in a high glucose DMEM medium containing 10% FBS.
  • the cells were seeded in 96-well cell culture plates at 25,000 cells per well.
  • the Fluo-8 working solution was prepared (Hank's balanced salt solution containing Fluo-82 ⁇ , probenecid 2 mM, tartrazine 1.5 mM, acid red 14 mM).
  • Example 91 Hypoglycemic effect of compounds on type II diabetes ob/ob mice
  • mice Male genetic type spontaneous type 2 diabetes ob/ob mice were housed in SPF animal rooms (temperature: 22-24 ° C, humidity: 45-80%, light: 150-300 Lx, 12 hours day and night), mice 6-7 weeks old prediction random blood glucose, fasting blood glucose and body weight, based on these indicators will ob / ob mice were divided into 3 groups, 8 per group, were orally administered 100m g / kg of the test compound HYH-013, 100 The mg/kg positive control was TAK875, and the control group was orally administered with 0.5% CMC. The blood glucose level was measured before administration and at 1h, 2h, 4h, 6h and 8h after administration. HYH-013 was observed for type II diabetes ob/ob mice. Hypoglycemic effect.
  • the results are shown in Table 2 and Figure 1.
  • the blood glucose of the control ob/ob mice was maintained at a high level before and after administration, and single oral administration of 100 mg/kg HYH-013 significantly reduced ob/ob.
  • Mouse blood sugar At 1 h after administration, the blood glucose of HYH-013 mice was significantly lower than that of the control group (P ⁇ 0.01), and the blood glucose decline rate was 22.3%.
  • the blood glucose of the positive control TAK-875 group did not decrease significantly compared with the control group; 2 h after administration At 4h, the blood glucose of HYH-013 group was significantly lower than that of the control group (PO.05), and the blood glucose decline rate was 26.3% and 23.4%, respectively.
  • the blood glucose of HYH-013 group was still significantly lower than that of the control group (P ⁇ 0.05, P ⁇ 0.01), and the blood glucose decreased. The rates were 24.7% and 26.8%, respectively, while the blood glucose of the positive control TAK875 group had no significant decrease compared with the control group. This suggests that HYH-013 has a significant hypoglycemic effect on type 2 diabetic ob/ob mice, and its effect lasts longer than TAK875.

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Abstract

L'invention porte sur un composé de phénylalanine ayant un groupe de liaison hétérocyclique azoté, qui permet d'abaisser considérablement la glycémie et de réguler l'activité métabolique sur les glycolipides, sur ses sels pharmaceutiquement acceptables ou stéréoisomères, sur des compositions pharmaceutiques comprenant le composé et sur l'utilisation du composé en préparation de médicaments pour des troubles diabétiques et du métabolisme des glycolipides, en particulier sur son utilisation en préparation de médicaments pour le traitement du diabète de type II. Le composé a une structure telle que représentée dans la formule I.
PCT/CN2014/075466 2013-04-16 2014-04-16 Composé de phénylalanine ayant un groupe de liaison hétérocyclique azoté, composition pharmaceutique associée, son procédé de préparation et son utilisation WO2014169817A1 (fr)

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