WO2011162267A1 - Nouveaux dérivés de thiophène-carboxamide et leur utilisation en tant que médicament - Google Patents

Nouveaux dérivés de thiophène-carboxamide et leur utilisation en tant que médicament Download PDF

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WO2011162267A1
WO2011162267A1 PCT/JP2011/064183 JP2011064183W WO2011162267A1 WO 2011162267 A1 WO2011162267 A1 WO 2011162267A1 JP 2011064183 W JP2011064183 W JP 2011064183W WO 2011162267 A1 WO2011162267 A1 WO 2011162267A1
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宣慶 春日井
徹 井土
久和 岩井
大輔 片岡
浩代 片岡
憲泰 加藤
祐花 久野
将和 小上
いずみ 後藤
由里枝 近藤
将夫 坂入
君枝 鈴木
直希 高橋
香里 近松
亘昭 鶴田
和包 長井
聡子 原田
尚樹 平松
広樹 藤枝
充弘 牧野
俊行 宮澤
美佳 三好
聖 村上
篤行 山下
信英 渡邉
マルティン ランク
ハンス―ユルゲン マルクス ザイフェルト
カーリナ クリスティーナ ボルフ
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株式会社 三和化学研究所
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic 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
    • A61P3/08—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
    • 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
    • C07D409/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to a novel thiophenecarboxamide derivative and its pharmaceutical use.
  • the compounds have various pharmaceutical uses as glucokinase activators.
  • Glucokinase (ATP: D-glucose 6-phosphotransferae, EC2.7.1.1.) Is one of four hexokinases (hexokinase IV) present in mammals.
  • Hexokinase is an enzyme that catalyzes the first step of glucose metabolism and converts glucose to glucose-6 phosphate.
  • Glucokinase is mainly expressed in liver and pancreatic ⁇ -cells and acts as a rate-limiting enzyme for glucose metabolism, and plays an important role in systemic glucose homeostasis.
  • Glucokinase has a low affinity for glucose and a Km value (8-15 mM) close to physiological blood glucose level. Also, glucokinase is not inhibited by physiological concentrations of glucose-6 phosphate. Therefore, glucokinase-mediated glucose metabolism increases when normoglycemia (5 mM) is increased to 10-15 mM by diet. From these results, it was considered that glucokinase works as a glucose sensor in the liver and pancreatic ⁇ cells.
  • glucokinase The role of glucokinase in animals was confirmed by studies using genetically modified animals. Mice that did not express glucokinase died of severe diabetes soon after birth, whereas mice that overexpressed glucokinase were reported to improve glucose tolerance. These studies confirmed that glucokinase actually has an important role in systemic glucose homeostasis.
  • Young adult-onset diabetes (MODY-2) is caused by a mutation of loss of function of the glucokinase gene, and a decrease in glucokinase activity causes an increase in blood glucose.
  • families with mutations that increase glucokinase activity have also been found, and these families show a fasting hypoglycemia due to elevated plasma insulin levels.
  • glucokinase works as a glucose sensor and plays an important role in blood glucose regulation, and blood glucose control using a glucose sensor system is considered to be a useful treatment in many type II diabetic patients.
  • a substance that activates glucokinase is expected to have an action of promoting insulin secretion in pancreatic ⁇ -cells, promoting glucose uptake in hepatocytes, and suppressing sugar release by enhancing the function of the glucose sensor. It is considered useful as a preventive or therapeutic agent for type 2 diabetes.
  • Non-patent Document 1 As a compound in which two 5-membered aromatic heterocycles are amide-bonded, Patent Document 1 reports a compound having a pyrrole ring, and Patent Document 2 reports a compound having an indole ring.
  • the structure is different from the thiophenecarboxamide derivative of the invention.
  • a thiophenecarboxamide derivative 2,5-dimethylthiophene-3-carboxylic acid thiazol-2-ylamide is sold as a reagent by Enamine (Ukraine).
  • the structure is different from the compound of the present invention having a benzene ring or a pyridine ring.
  • the present invention provides a compound having a glucokinase activating action, and is based on the glucokinase activating action, such as diabetes or diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, ischemic heart disease, or It is an object to provide a preventive or therapeutic agent for chronic complications of diabetes such as arteriosclerosis.
  • the present inventors consider that a compound having a new basic structure is effective as a means for solving the above problems, and eagerly researched to create a novel glucokinase activator. Repeated.
  • the compound represented by the following general formula (I) has a very excellent glucokinase activation action, and also has excellent properties in terms of physical properties as a pharmaceutical such as solubility, was found to be a safe and useful medicine excellent in the difference between the side effects (effects on hERG and CYP) and drug efficacy, and the present invention was completed.
  • X represents a nitrogen atom or CR 2
  • R 2 represents a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group, or a C 1 -C 6 alkylthio group
  • Y represents a nitrogen atom or CR 3
  • R 3 represents a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, or a C 1 -C 6 alkylthio group.
  • X is a nitrogen atom
  • Y is not a nitrogen atom
  • Z represents a nitrogen atom or CR 4
  • R 4 represents a hydrogen atom, a halogen atom, or (CH 2 ) m -R 5 .
  • m represents an integer of 1 to 6
  • R 5 represents a hydroxy group or a C 1 -C 6 alkoxy group
  • R 1 represents an amino group, a nitrile group, an acetyl group, a mesyl group, a carbamoyl group, a sulfamoyl group, CONH- (CH 2 ) n -AR 6 or SO 2 NH- (CH 2 ) n -R 7 is meant.
  • n is an integer of 1 to 6
  • A is absent or an oxygen atom or a sulfur atom
  • R 6 is a hydrogen atom, a C 1 -C 6 alkyl group, or a C 1 -C 6 hydroxy group
  • R 7 represents a hydroxy group or a C 1 -C 6 alkoxy group] Or a pharmacologically acceptable salt thereof, and these compounds are hereinafter referred to as “the compounds of the present invention”.
  • a compound wherein Z is C— (CH 2 ) 2 —OH or C— (CH 2 ) 3 —OH, and R 1 is an amino group, a carbamoyl group, or a mesyl group.
  • a compound wherein Z is C— (CH 2 ) 2 —OH and R 1 is a mesyl group.
  • Z is CH or CF
  • R 1 is CONH- (CH 2 ) 2 -OR 6
  • R 6 is a C 1 -C 3 alkyl group or C 1 -C 3 hydroxyalkyl.
  • R 1 is CONH— (CH 2 ) 2 —O— (CH 2 ) 2 —OH.
  • X is a nitrogen atom
  • Y is CH or a C— (C 1 -C 3 alkyl) group
  • Z is C— (CH 2 ) 2 —OH
  • R 1 is A compound that is a mesyl group.
  • X is a nitrogen atom
  • Y is CH or a C- (C 1 -C 3 alkyl) group
  • Z is CH or CF
  • R 1 is CONH- (CH 2 ).
  • X is CF or C—Cl
  • Y is CH
  • Z is CH or CF
  • R 1 is CONH— (CH 2 ) 2 —O— (CH 2 ) 2.
  • the present invention also provides a compound represented by the following general formula (II), which is an intermediate of the compound of the present invention represented by the above general formula (I).
  • Z 1 represents a nitrogen atom or CR 10
  • R 10 represents a hydrogen atom, a halogen atom, or (CH 2 ) m -R 11 .
  • R 11 represents an optionally protected hydroxy group or a C 1 -C 6 alkoxy group
  • R 8 represents a nitro group, an amino group, a nitrile group, an acetyl group, It means mesyl group, carbamoyl group, sulfamoyl group, CO 2 R 12 , CONH— (CH 2 ) n —AR 13 , or SO 2 NH— (CH 2 ) n —R 14 .
  • R 12 represents a hydrogen atom or a protecting group for a carboxyl group
  • n represents an integer of 1 to 6
  • A represents an absent or oxygen atom or a sulfur atom
  • R 13 represents a hydrogen atom, C 1 -C 6 alkyl group, hydroxy protecting group, or C 1 -C 6 hydroxyalkyl group that may be protected
  • R 14 may be protected hydroxy group or C 1 -C 6 Means an alkoxy group
  • R 9 means a hydrogen atom or a protecting group for a carboxyl group
  • the present invention further provides a pharmaceutical composition containing the compound of the present invention as an active ingredient. That is, the pharmaceutical composition of the present invention is used for the prevention or treatment of diabetes.
  • the compound of the present invention has an excellent glucokinase activation action, and is a chronic complication of diabetes such as diabetes or diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, ischemic heart disease, or arteriosclerosis It is useful as a preventive or therapeutic agent.
  • the present invention also provides a safe and useful medicament excellent in the difference between various side effects (effects on hERG and CYP) and drug efficacy.
  • X is a nitrogen atom or CR 2
  • R 2 is a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group, or a C 1 -C 6 alkylthio group
  • Y is a nitrogen atom or CR 3
  • R 3 is a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, or a C 1 -C 6 alkylthio group.
  • X is preferably a nitrogen atom, C—Cl, or CF
  • Y is preferably CH or a C— (C 1 -C 3 ) alkyl group.
  • X is preferably a nitrogen atom
  • Y is preferably CH or a C— (C 1 -C 3 ) alkyl group
  • X is C—Cl or CF
  • Y is preferably CH.
  • Z is a nitrogen atom or CR 4 , R 4 is a hydrogen atom, a halogen atom, or (CH 2 ) m -R 5 , m is an integer of 1 to 6, and R 5 is a hydroxy group or C 1 -C 6 R 1 is an amino group, a nitrile group, an acetyl group, a mesyl group, a carbamoyl group, a sulfamoyl group, CONH- (CH 2 ) n -AR 6 , or SO 2 NH- (CH 2 ) n- R 7 , n is an integer of 1 to 6, A is absent, an oxygen atom, or a sulfur atom, R 6 is a hydrogen atom, a C 1 -C 6 alkyl group, or C 1 — A C 6 hydroxyalkyl group and R 7 is a hydroxy group or a C 1 -C 6 alkoxy group; Among these, Z is C— (CH 2 ) 2
  • a particularly preferred compound of the present invention is represented by the general formula (I), wherein X is a nitrogen atom, Y is CH or a C- (C 1 -C 3 alkyl) group, and Z is C- (CH 2 ) 2- OH and R 1 is a mesyl group.
  • Another particularly preferred compound of the present invention is a compound represented by the general formula (I), wherein X is a nitrogen atom, Y is CH or a C- (C 1 -C 3 alkyl) group, and Z is CH or CF.
  • R 1 is CONH— (CH 2 ) 2 —O— (CH 2 ) 2 —OH.
  • halogen atom means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • C1-C6 alkyl group means a linear or branched alkyl group composed of 1 to 6 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, an i-propyl group, n-butyl group, i-butyl group, s-butyl group, t-butyl group, n-pentyl group, i-pentyl group, neo-pentyl group, t-pentyl group, n-hexyl group, i-hexyl group, Examples thereof include 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group and the like.
  • C1-C6 alkoxy group means an —O— (C1-C6 alkyl) group, for example, methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-butoxy group, i-butoxy group.
  • C1-C6 alkylthio group means a —S— (C1-C6 alkyl) group.
  • the “C1-C6 hydroxyalkyl group” means a (C1-C6 alkylene) -OH group, and the “C1-C6 alkylene” means a linear alkylene composed of 1 to 6 carbon atoms. Meaning, for example, methylene, ethylene, n-propylene, n-butylene and the like.
  • “Pharmaceutically acceptable salt” means a salt that retains the biological effectiveness and properties of the compound represented by the general formula (I) and that is not biologically or otherwise inconvenient. To do. Such pharmacologically acceptable salts are included in the scope of the present invention.
  • Pharmacologically acceptable salts include inorganic acid addition salts (for example, salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.), organic acid addition salts (for example, methanesulfonic acid, p- Toluenesulfonic acid, acetic acid, oxalic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid, salt with malic acid), salt with amino acid (for example, salt with lysine, arginine, etc.), alkali metal addition salt (Eg, salts with sodium, potassium, etc.), alkaline earth metal addition salts (eg, salts with calcium, magnesium, etc.), organic amine addition salts (eg, salts with diethylamine, diethanolamine, piperazine, etc.), etc. It is done. The formation reaction of these addition salts can be performed according to a conventional method.
  • organic acid addition salts for example, me
  • the compounds of the present invention also include prodrugs that mean compounds that are converted to the above general formula (I) by reactions with enzymes, gastric acid, and the like under physiological conditions in vivo, and various prodrugs are known in the art. It is.
  • a prodrug when the compound represented by the general formula (I) has a hydroxy group, a compound in which the hydroxy group is acylated (for example, acetylation, propionylation, isopropoxycarbonylation, methoxycarbonylation) , Pivaloyloxymethylated compounds) and the like.
  • the compound represented by the general formula (I) which is the compound of the present invention can be produced by combining the methods shown in the following reaction process formulas I to VII, the methods described in Examples 66 to 74, or known methods. it can.
  • reaction Process Formula I [Wherein, Z 2 is a nitrogen atom, CH, or C-halogen atom, R 15 is a protecting group for a carboxyl group, and other symbols are as defined above]
  • Step I-1 The compound represented by the general formula (IIa) and the compound represented by the general formula (III) are added in an appropriate solvent (for example, N, N-dimethylformamide, methylene chloride, tetrahydrofuran, etc.) with additives (diisopropylethylamine, 4- Reaction in the presence or absence of dimethylaminopyridine, 1-hydroxy-1H-benzotriazole, etc.) using a condensing agent (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, dicyclohexylcarbodiimide, etc.) Gives a compound of the general formula (IV).
  • the reaction temperature is from ⁇ 20 ° C.
  • the compound represented by the general formula (IIa) is converted into an acid chloride using a chlorinating agent (for example, thionyl chloride, oxalyl chloride) in an appropriate solvent (for example, toluene, methylene chloride, etc.)
  • a chlorinating agent for example, thionyl chloride, oxalyl chloride
  • an appropriate solvent for example, toluene, methylene chloride, etc.
  • the compound represented by (III) is reacted with a base (eg, triethylamine, N, N-diethylaniline, etc.) in an appropriate solvent (eg, toluene, methylene chloride, tetrahydrofuran, N, N-dimethylformamide, etc.).
  • a base eg, triethylamine, N, N-diethylaniline, etc.
  • an appropriate solvent eg, toluene, methylene chloride,
  • the reaction temperature is from ⁇ 20 ° C. to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours.
  • the compound represented by general formula (III) can be obtained as a commercial item, or can be manufactured using a well-known method.
  • Step I-2 Referring to the method described in “Protecting Groups in Organic Synthesis, 3rd Edition , Wiley (1999) ", by removing the protecting group R 15 of the compound represented by formula (IV), the general formula (V) The compound represented is obtained.
  • Step I-3 The compound represented by the general formula (V) and the compound represented by the general formula (VI) are added in an appropriate solvent (for example, N, N-dimethylformamide, methylene chloride, tetrahydrofuran, etc.) with additives (diisopropylethylamine, 4- Reaction in the presence or absence of dimethylaminopyridine, 1-hydroxy-1H-benzotriazole, etc.) using a condensing agent (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, dicyclohexylcarbodiimide, etc.) givess a compound represented by the general formula (Ia).
  • the reaction temperature is from ⁇ 20 ° C. to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours.
  • the compound represented by general formula (VI) can be obtained as a commercial item, or can be manufactured combining a well-known method.
  • Step II-1 The compound represented by the general formula (IIc) and the compound represented by the general formula (VI) are added in an appropriate solvent (for example, N, N-dimethylformamide, methylene chloride, tetrahydrofuran, etc.) with additives (diisopropylethylamine, 4- Reaction in the presence or absence of dimethylaminopyridine, 1-hydroxy-1H-benzotriazole, etc.) using a condensing agent (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, dicyclohexylcarbodiimide, etc.) givess a compound represented by the general formula (IId).
  • the reaction temperature is from ⁇ 20 ° C. to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours.
  • Step II-2 The compound represented by the general formula (IIe) is obtained by removing the protecting group R 16 of the compound represented by the general formula (IId) with reference to the method described in “Protecting Groups in Organic Synthesis”. .
  • Step II-3 The compound represented by the general formula (IIe) and the compound represented by the general formula (III) are added in an appropriate solvent (for example, N, N-dimethylformamide, methylene chloride, tetrahydrofuran, etc.) with additives (diisopropylethylamine, 4- Reaction in the presence or absence of dimethylaminopyridine, 1-hydroxy-1H-benzotriazole, etc.) using a condensing agent (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, dicyclohexylcarbodiimide, etc.) givess a compound represented by the general formula (Ib).
  • the reaction temperature is from ⁇ 20 ° C. to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours.
  • reaction Process III The compound represented by the general formula (IIa) or (IIc) can be produced by the method of reaction process formula III shown below.
  • reaction Process III [Wherein, R 17 is an alkyl group, a hydroxy group, or an alkoxy group, R 18 is a chlorine atom, a bromine atom, an iodine atom, or a trifluoromethanesulfonate group, and other symbols are as defined above. ]
  • Step III-1 The compound represented by the general formula (VII) and the compound represented by the general formula (VIII) in an appropriate solvent (eg, dimethoxyethane, N, N-dimethylformamide, acetonitrile, tetrahydrofuran, etc.) Palladium catalyst (tetrakistriphenylphosphine palladium (0), 1,1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane in the presence of aqueous solution of potassium, cesium carbonate, potassium carbonate, sodium carbonate, etc.) By reacting with a complex, trans-dichlorobis (triphenylphosphine) palladium (II), palladium (II) acetate, etc., a compound represented by the general formula (IIf) is obtained.
  • an appropriate solvent eg, dimethoxyethane, N, N-dimethylformamide, acetonit
  • the reaction temperature is from 0 ° C. to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours.
  • the compound represented by the general formula (VII) or the general formula (VIII) is available as a commercial product, or can be produced by combining the methods described in Reference Examples 1 to 5 or known methods. it can.
  • Step III-2 The compound represented by the general formula (IX) and the compound represented by the general formula (X) are added in an appropriate solvent (for example, dimethoxyethane, N, N-dimethylformamide, acetonitrile, tetrahydrofuran, etc.)
  • Palladium catalyst tetrakistriphenylphosphinepalladium (0), 1,1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane in the presence of aqueous solution of potassium, cesium carbonate, potassium carbonate, sodium carbonate, etc.
  • the reaction temperature is from 0 ° C. to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours.
  • the compound represented by the general formula (IX) or the general formula (X) is available as a commercial product, the method described in Reference Example 7, Reference Example 24, or Reference Example 25, or a known method Can be manufactured in combination.
  • Step III-3 The compound represented by the general formula (IIa) is obtained by removing the protecting group R 16 of the compound represented by the general formula (IIf) with reference to the method described in “Protecting Groups in Organic Synthesis”. .
  • Step III-4 The compound represented by the general formula (IIc) is obtained by removing the protecting group R 15 of the compound represented by the general formula (IIf) with reference to the method described in the above “Protecting Groups in Organic Synthesis”. .
  • the compound represented by the general formula (IIc) can also be produced by the method of the reaction process formula IV shown below. [Reaction Process IV] [The symbols in the formula are as defined above.]
  • Step IV-1 Add the compound represented by the general formula (XI) and the compound represented by the general formula (VIII) in an appropriate solvent (for example, dimethoxyethane, N, N-dimethylformamide, acetonitrile, tetrahydrofuran, etc.) Palladium catalyst (tetrakistriphenylphosphine palladium (0), 1,1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane in the presence of aqueous solution of potassium, cesium carbonate, potassium carbonate, sodium carbonate, etc.) By reacting with a complex, trans-dichlorobis (triphenylphosphine) palladium (II), palladium (II) acetate, etc., a compound represented by the general formula (XII) is obtained.
  • an appropriate solvent for example, dimethoxyethane, N, N-dimethylformamide, aceton
  • the reaction temperature is from 0 ° C. to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours.
  • the compound represented by general formula (XI) can be obtained as a commercial item, or can be manufactured combining a well-known method.
  • Step IV-2 Add the compound represented by the general formula (XIII) and the compound represented by the general formula (X) in an appropriate solvent (for example, dimethoxyethane, N, N-dimethylformamide, acetonitrile, tetrahydrofuran, etc.) Palladium catalyst (tetrakistriphenylphosphine palladium (0), 1,1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane in the presence of aqueous solution of potassium, cesium carbonate, potassium carbonate, sodium carbonate, etc.) By reacting with a complex, trans-dichlorobis (triphenylphosphine) palladium (II), palladium (II) acetate, etc., a compound represented by the general formula (XII) is obtained.
  • the reaction temperature is from 0 ° C. to the boiling point of the solvent, and the reaction time is from 30 minutes to 48
  • Step IV-3 Sodium chlorite and sodium dihydrogen phosphate in a suitable solvent (such as t-butyl alcohol) in the presence of an additive (2-methyl-2-butene, etc.) in a compound represented by general formula (XII)
  • a suitable solvent such as t-butyl alcohol
  • an additive (2-methyl-2-butene, etc.
  • the compound represented by the general formula (IIc) is obtained by oxidation using The reaction temperature is from ⁇ 20 ° C. to the boiling point of the solvent, and the reaction time is from 10 minutes to 48 hours.
  • Step V-1 Using the compound represented by the general formula (XIV) and the compound represented by the general formula (VI) in a suitable solvent (for example, toluene, methylene chloride, tetrahydrofuran, etc.) using a base (for example, triethylamine, dimethylaminopyridine, etc.) To obtain a compound represented by the general formula (XV).
  • a suitable solvent for example, toluene, methylene chloride, tetrahydrofuran, etc.
  • a base for example, triethylamine, dimethylaminopyridine, etc.
  • the reaction temperature is from ⁇ 20 ° C. to the boiling point of the solvent, and the reaction time is from 10 minutes to 48 hours.
  • the compound represented by the general formula (XIV) is available as a commercial product, or can be produced by combining known methods.
  • Step V-2 Add the compound represented by the general formula (XV) and the compound represented by the general formula (X) in an appropriate solvent (for example, dimethoxyethane, N, N-dimethylformamide, acetonitrile, tetrahydrofuran, etc.) Palladium catalyst (tetrakistriphenylphosphinepalladium (0), 1,1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane in the presence of potassium, cesium carbonate, potassium carbonate, sodium carbonate, etc.) By reacting with a complex, trans-dichlorobis (triphenylphosphine) palladium (II), palladium (II) acetate, etc., a compound represented by the general formula (IIg) is obtained.
  • the reaction temperature is from 0 ° C. to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours.
  • Step V-3 The compound represented by the general formula (IIh) is obtained by removing the protecting group R 16 of the compound represented by the general formula (IIg) with reference to the method described in the above “Protecting Groups in Organic Synthesis”. .
  • Step V-4 The compound represented by the general formula (IIh) and the compound represented by the general formula (III) are added in an appropriate solvent (for example, N, N-dimethylformamide, methylene chloride, tetrahydrofuran, etc.) with additives (diisopropylethylamine, 4- Reaction in the presence or absence of dimethylaminopyridine, 1-hydroxy-1H-benzotriazole, etc.) using a condensing agent (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, dicyclohexylcarbodiimide, etc.) givess a compound represented by the general formula (Ic).
  • the reaction temperature is from ⁇ 20 ° C. to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours.
  • reaction process formula VI [The symbols in the formula are as defined above.]
  • Step VI-1 Add the compound represented by the general formula (XVI) and the compound represented by the general formula (X) in an appropriate solvent (for example, dimethoxyethane, N, N-dimethylformamide, acetonitrile, tetrahydrofuran, etc.) Palladium catalyst (tetrakistriphenylphosphinepalladium (0), 1,1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane in the presence of potassium, cesium carbonate, potassium carbonate, sodium carbonate, etc.) By reacting with a complex, trans-dichlorobis (triphenylphosphine) palladium (II), palladium (II) acetate, etc., a compound represented by the general formula (IIi) is obtained.
  • the reaction temperature is from 0 ° C. to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours.
  • Step VI-2 The compound represented by the general formula (IIj) is obtained by reacting the compound represented by the general formula (IIi) with an iron powder in an appropriate solvent (for example, a mixed solvent of acetic acid and water). .
  • an appropriate solvent for example, a mixed solvent of acetic acid and water.
  • the reaction temperature is from 0 ° C. to the boiling point of the solvent, and the reaction time is from 5 minutes to 48 hours.
  • Step VI-3 By reacting the compound represented by the general formula (IIj) with nitrous acid or a salt thereof in an appropriate solvent (for example, water, acetic acid, a mixed solvent thereof, etc.) under hydrochloric acid in accordance with a conventional method. After being converted to a diazonium salt, it is represented by the general formula (XVII) by reacting with copper (I) chloride and an aqueous sulfur dioxide solution in an appropriate solvent (for example, water, acetic acid, a mixed solvent thereof, etc.). A compound is obtained. The reaction temperature is from ⁇ 20 ° C. to the boiling point of the solvent, and the reaction time is from 5 minutes to 48 hours.
  • an appropriate solvent for example, water, acetic acid, a mixed solvent thereof, etc.
  • Step VI-4 A compound represented by the general formula (XVII) and a compound represented by the general formula (VI) are used in a suitable solvent (for example, toluene, methylene chloride, tetrahydrofuran, etc.) using a base (for example, triethylamine, dimethylaminopyridine, etc.).
  • a suitable solvent for example, toluene, methylene chloride, tetrahydrofuran, etc.
  • a base for example, triethylamine, dimethylaminopyridine, etc.
  • R 19 represents a nitro group, an amino group, a nitrile group, an acetyl group, a mesyl group, a carbamoyl group, or a sulfamoyl group, and other symbols are as defined above.
  • Step VII-1 Add the compound represented by the general formula (XVIII) and the compound represented by the general formula (X) in an appropriate solvent (for example, dimethoxyethane, N, N-dimethylformamide, acetonitrile, tetrahydrofuran, etc.) Palladium catalyst (tetrakistriphenylphosphinepalladium (0), 1,1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane in the presence of aqueous solution of potassium, cesium carbonate, potassium carbonate, sodium carbonate, etc.) By reacting with a complex, trans-dichlorobis (triphenylphosphine) palladium (II), palladium (II) acetate, etc., a compound represented by the general formula (IIk) is obtained.
  • an appropriate solvent for example, dimethoxyethane, N, N-dimethylformamide, aceton
  • the reaction temperature is from 0 ° C. to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours.
  • the compound represented by the general formula (XVIII) can be produced by combining the methods described in Reference Examples 40 to 49, Reference Example 58, Reference Examples 61 to 62, or known methods.
  • Step VII-2 Add the compound represented by the general formula (XIX) and the compound represented by the general formula (VIII) in an appropriate solvent (for example, dimethoxyethane, N, N-dimethylformamide, acetonitrile, tetrahydrofuran, etc.) Palladium catalyst (tetrakistriphenylphosphine palladium (0), 1,1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane in the presence of aqueous solution of potassium, cesium carbonate, potassium carbonate, sodium carbonate, etc.) By reacting with a complex, trans-dichlorobis (triphenylphosphine) palladium (II), palladium (II) acetate, etc., a compound represented by the general formula (IIk) is obtained.
  • the reaction temperature is from 0 ° C. to the boiling point of the solvent, and the reaction time is from 30 minutes
  • Step VII-3 The compound represented by the general formula (II l) is obtained by removing the protecting group R 16 of the compound represented by the general formula (IIk) with reference to the method described in the above “Protecting Groups in Organic Synthesis”. It is done.
  • Step VII-4 The compound represented by the general formula (II l) and the compound represented by the general formula (III) are added in an appropriate solvent (for example, N, N-dimethylformamide, methylene chloride, tetrahydrofuran, etc.) with additives (diisopropylethylamine, 4 In the presence or absence of -dimethylaminopyridine, 1-hydroxy-1H-benzotriazole, etc.) using a condensing agent (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, dicyclohexylcarbodiimide, etc.)
  • an appropriate solvent for example, N, N-dimethylformamide, methylene chloride, tetrahydrofuran, etc.
  • additives diisopropylethylamine, 4 In the presence or absence of -dimethylaminopyridine, 1-hydroxy-1H-benzotriazole, etc.
  • a condensing agent (1
  • the reaction temperature is from ⁇ 20 ° C. to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours.
  • the compound represented by the general formula (II l) is converted into an acid chloride using a chlorinating agent (eg thionyl chloride, oxalyl chloride) in a suitable solvent (eg toluene, methylene chloride, etc.) Reaction with a compound represented by the formula (III) using a base (eg, triethylamine, N, N-diethylaniline, etc.) in an appropriate solvent (eg, toluene, methylene chloride, tetrahydrofuran, N, N-dimethylformamide, etc.) To obtain the compound represented by the general formula (Id).
  • the reaction temperature is from ⁇ 20 ° C. to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours.
  • substituents for example, a hydroxyl group, a carboxylic acid group, etc.
  • substituents for example, a hydroxyl group, a carboxylic acid group, etc.
  • substituents contained in the compound of the present invention and the compound used for producing the compound have an appropriate protecting group at the raw material or intermediate stage. Introducing the compound may be effective in producing the compound, and the protecting group described in the above “Protecting Groups in Organic Synthesis” may be appropriately selected and used as necessary.
  • a commonly used method can be used. For example, solvent extraction, ion exchange resin, column chromatography using silica gel, alumina or the like as a carrier, high performance liquid chromatography (HPLC) fractionation, thin layer chromatography, scavenger resin, recrystallization, etc. can be used.
  • HPLC high performance liquid chromatography
  • isolation and purification methods can be performed alone or in combination. Isolation and purification may be performed for each reaction or after completion of several reactions.
  • the compound of the present invention acts as a glucokinase activator, it can be used as a pharmaceutical composition.
  • the pharmaceutical composition is useful as a prophylactic or therapeutic agent for diabetes or diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, ischemic heart disease, or chronic complications of diabetes such as arteriosclerosis.
  • various dosage forms described in the “Japanese Pharmacopoeia” preparation general rules can be selected according to the purpose. For example, when it is formed into a tablet form, it is generally sufficient to select an orally ingestible component used in the field. For example, excipients such as lactose, crystalline cellulose, sucrose, potassium phosphate and the like are examples. Furthermore, if desired, various additives commonly used in the field of pharmaceutical preparations such as a binder, a disintegrant, a lubricant, and an aggregation inhibitor may be blended.
  • the amount of the compound of the present invention contained as an active ingredient in the preparation of the present invention is not particularly limited and is appropriately selected from a wide range.
  • the dose of the active ingredient compound is appropriately determined depending on its usage, patient age, gender and other conditions, and the degree of disease.
  • the amount of the compound of the present invention is about 1 ⁇ g / kg body weight per day.
  • the dose can be appropriately administered in a range of ⁇ 100 mg divided into 1 to 4 times a day.
  • the dosage and frequency are determined in view of the relevant conditions including the degree of the condition to be treated, the choice of the compound to be administered and the selected route of administration, the dosage range and frequency are It is not intended to limit the scope of the invention.
  • the nuclear magnetic resonance ( 1 H-NMR) spectra in the following examples and reference examples are described with chemical shift values expressed as ⁇ values (ppm) using tetramethylsilane as a standard substance.
  • the splitting pattern is indicated by “s” for singlets, “d” for doublets, “dd” for double doublets, “t” for triplets, “m” for multiplets, and “brs” for broad singlets.
  • Mass spectrometry was performed by electrospray ionization (ESI).
  • methyl group is “Me”
  • ethyl group is “Et”
  • i-propyl group is “i-Pr”
  • methanesulfonyl group is “Ms”
  • acetyl group is “Ac”
  • 2-tetrahydropyranyl group Is “THP” and the pivaloyl group is “Piv”.
  • Example 1 5- (2-Ethoxycarbonylphenyl) -2-methylthiophene-3-carboxylic acid benzyl ester 5-bromo-2-methylthiophene-3-carboxylic acid benzyl ester (1.96 g) in 1,2-dimethoxy under argon atmosphere Dissolve in ethane (50 mL), ethyl 2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate (2.26 g), potassium carbonate (3.55 g) and 1 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex (257 mg) was added, and the mixture was stirred at 85 ° C.
  • Example 2 5- (2-Ethoxycarbonylphenyl ) -2-methylthiophene-3-carboxylic acid benzyl ester (2.66 g) in ethanol under argon atmosphere (50.0 mL) and 10% palladium on carbon (500 mg) was added. After substituting the inside of reaction container with hydrogen, it stirred at 50 degreeC for 4 hours. The reaction vessel was purged with argon, filtered through celite, washed with ethyl acetate, and concentrated. Diethyl ether was added to the resulting residue, and the precipitated crystals were collected by filtration and washed with diethyl ether to obtain the title compound (1.53 g) as a white powder.
  • Example 3 2- (4-Benzyloxycarbonyl-5-methylthiophen-2-yl) benzoic acid 5- (2-formylphenyl) -2-methylthiophene-3-carboxylic acid benzyl ester (3.94 g) was added to t-butyl alcohol ( 40.0 mL), and 2-methyl-2-butene was added and stirred.
  • Sodium chlorite (9.19 g) and sodium dihydrogen phosphate (18.3 g) were dissolved in distilled water (80 mL) and added dropwise, followed by stirring for 2.5 hours. Distilled water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • Example 5 5- (2-Methoxycarbonylphenyl) -2-methylthiophene- 3-carboxylic acid benzyl ester (4.03 g) in ethanol under argon atmosphere (80.0 mL) and 10% palladium on carbon (800 mg) was added. After substituting the inside of reaction container with hydrogen, it stirred at 50 degreeC for 4 hours. After replacing the inside of the reaction vessel with argon, the reaction solution was filtered through celite, washed with ethyl acetate, and concentrated. Diethyl ether was added to the resulting residue, and the precipitated crystals were collected by filtration and washed with diethyl ether to give the title compound (3.01 g) as a white powder.
  • Example 6 3- (4-Benzyloxycarbonyl-5-methylthiophen-2-yl) picolinic acid methyl ester Under argon atmosphere, 5-bromo-2-methylthiophene-3-carboxylic acid benzyl ester (1.56 g) was added to tetrahydrofuran (16.0 mL). ) And cooled to -40 ° C. A 0.78 M tetrahydrofuran solution (6.50 mL) of isopropylmagnesium bromide was added dropwise, followed by stirring for 1 hour. Triisopropyl borate (350 ⁇ L) was added dropwise at ⁇ 40 ° C., followed by stirring at room temperature for 1 hour.
  • 3-bromopicolinic acid methyl ester (414 mg) was dissolved in tetrahydrofuran (8.00 mL), and the resulting crude product (624 mg) and tetrakistriphenylphosphine palladium (0) (66.2 mg) were added. For 10 minutes. A 2.0 M aqueous sodium carbonate solution (4.79 mL) was added, and the mixture was stirred at 70 ° C. for 17 hours. After cooling to room temperature, the insoluble material was filtered and washed with ethyl acetate. The organic layer was washed with distilled water and saturated brine, and then dried over anhydrous sodium sulfate.
  • Example 7 5- (2-Methoxycarbonylpyridin-3-yl) -2-methylthiophene-3-carboxylate under argon atmosphere, 3- (4-benzyloxycarbonyl-5-methylthiophen-2-yl) picolinic acid methyl ester ( 645 mg) was dissolved in ethanol (9.00 mL), and 10% palladium carbon (130 mg) and acetic acid (3.00 mL) were added. After substituting the inside of reaction container with hydrogen, it stirred at 70 degreeC for 14 hours. After replacing the inside of the reaction vessel with argon, the reaction solution was filtered through celite, washed with ethyl acetate, and concentrated under reduced pressure.
  • Example 8 N- (5-chlorothiazol-2-yl) -5- [2- (2-methoxyethylcarbamoyl) phenyl] -2-methylthiophene-3-carboxamide 2- (4- (5-chlorothiazol -2-yl) Rucarbamoyl) -5-methylthiophen-2-yl) benzoic acid (37.9 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (38.3 mg) and 1-hydroxy-1H-benzotriazole (27.0 mg) ) was dissolved in N, N-dimethylformamide (500 ⁇ L) and stirred at room temperature for 30 minutes.
  • Example 8 With reference to the method of Example 8, the compound was synthesized according to the following reaction formula. The synthesized compounds are shown in Table 5, and the data are shown in Table 6.
  • Example 21 5- (2-carboxyphenyl) -2-methylthiophene-3-carboxylic acid methyl ester
  • 5- (2-formyl (Phenyl) -2-methylthiophene-3-carboxylic acid methyl ester was used in the same manner as in Example 3 to obtain the title compound.
  • Example 22 3- (4-Methoxycarbonyl-5-methylthiophen-2-yl) picolinic acid benzyl ester Under an argon atmosphere, 3-bromopicolinic acid benzyl ester (4.12 g) was dissolved in tetrahydrofuran (35.0 mL), and (4- ( Methoxycarbonyl) -5-methylthiophen-2-yl) boronic acid (4.22 g), 2.0 M aqueous sodium carbonate solution (17.6 mL) and tetrakis (triphenylphosphine) palladium (0) (489 mg) were added at 70 ° C. Stir for 15 hours.
  • Example 23 3- (4-Methoxycarbonyl-5-methylthiophen-2-yl) picolinic acid in an argon atmosphere was mixed with 3- (4-methoxycarbonyl-5-methylthiophen-2-yl) picolinic acid benzyl ester (1.00 g) in ethanol. (15.0 mL), 10% palladium carbon (200 mg) was added, and the mixture was stirred at room temperature for 10 minutes. After substituting the inside of reaction container with hydrogen, it stirred at 70 degreeC for 4 hours. The reaction mixture was filtered through celite, washed with ethyl acetate, concentrated under reduced pressure, and dried to obtain the title compound (730 mg).
  • Example 24 Instead of 2-fluoro-6- (4-methoxycarbonyl-5-methylthiophen-2-yl) benzoic acid 5- (2-formylphenyl) -2-methylthiophene-3-carboxylic acid benzyl ester, 5- ( 3-Fluoro-2-formylphenyl) -2-methylthiophene-3-carboxylic acid methyl ester was used in the same manner as in Example 3 to obtain the title compound.
  • Example 25 N- (3-ethyl-1,2,4-thiadiazol-5-yl) -5- [2- (2-methoxyethylcarbamoyl) phenyl] -2-methylthiophene-3-carboxamide under an argon atmosphere, 5- [ 2- (2-methoxyethylcarbamoyl) phenyl] -2-methylthiophene-3-carboxylic acid (50 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (60 mg) and 1-hydroxy-1H— Benzotriazole (48 mg) was dissolved in N, N-dimethylformamide (0.50 mL) and stirred at room temperature for 1 hour.
  • Example 25 With reference to the method of Example 25, the compound was synthesized according to the following reaction formula. The synthesized compounds are shown in Table 11 and the data are shown in Table 12.
  • Example 31 5- [3-Fluoro-2- [2- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] ethylcarbamoyl] phenyl] -2-methylthiophene-3-carboxylic acid methyl ester under argon atmosphere 2 -Fluoro-6- (4-methoxycarbonyl-5-methylthiophen-2-yl) benzoic acid (369 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (480 mg) and 1-hydroxy-1H -Benzotriazole (384 mg) was dissolved in N, N-dimethylformamide (4.00 mL) and stirred at room temperature for 1 hour.
  • Example 32 2-Methyl-5- [2- [2- (tetrahydro-2H-pyran-2-yloxy) ethylcarbamoyl] phenyl] thiophene-3-carboxylic acid methyl ester 2- [2- (tetrahydro-2H-pyran-2- The title compound was obtained in the same manner as in Example 31 except that 2- (tetrahydro-2H-pyran-2-yloxy) ethanamine was used instead of (yloxy) ethoxy] ethanamine.
  • Example 33 2-Methyl-5- [2- [2- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] ethylcarbamoyl] pyridin-3-yl] thiophene-3-carboxylic acid methyl ester 2-fluoro-6 Similar to Example 31 except that 3- (4-methoxycarbonyl-5-methylthiophen-2-yl) picolinic acid was used instead of-(4-methoxycarbonyl-5-methylthiophen-2-yl) benzoic acid. Reaction was carried out by the method to obtain the title compound.
  • Example 34 5- [3-Fluoro-2- [2- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] ethylcarbamoyl] phenyl] -2-methylthiophene-3-carboxylic acid 5- [3-fluoro- 2- [2- [2- (Tetrahydro-2H-pyran-2-yloxy) ethoxy] ethylcarbamoyl] phenyl] -2-methylthiophene-3-carboxylic acid methyl ester (1.46 g) dissolved in tetrahydrofuran (15.0 mL) Distilled water (15.0 mL) and lithium hydroxide monohydrate (395 mg) were added, and the mixture was stirred at 50 ° C.
  • Example 34 With reference to the method of Example 34, the compound was synthesized according to the following reaction formula. The synthesized compounds are shown in Table 13, and the data are shown in Table 14.
  • Example 37 With reference to the method of Example 37, the compound was synthesized according to the following reaction formula.
  • the synthesized compounds are shown in Table 17, and the data are shown in Table 18.
  • Example 42 instead of 2-methyl-5- [2- [2- (tetrahydro-2H-pyran-2-yloxy) ethylsulfamoyl] phenyl] thiophene-3-carboxylic acid methyl ester 2-chloro-6-fluorobenzaldehyde, The title compound was obtained in the same manner as in Reference Example 26 using 2-bromo-N- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] benzenesulfonamide.
  • Example 43 N- (5-chlorothiazol-2-yl) -5- [2- (2-hydroxyethylsulfamoyl) phenyl] -2-methylthiophene-3-carboxamide N- (5-chlorothiazol-2-yl) Instead of -5- [3-fluoro-2- [2- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] ethylcarbamoyl] phenyl] -2-methylthiophene-3-carboxamide, N- (5 Example 37 using -chlorothiazol-2-yl) -2-methyl-5- [2- [2- (tetrahydro-2H-pyran-2-yloxy) ethylsulfamoyl] phenyl] thiophene-3-carboxamide The reaction was carried out in the same manner as in to give the title compound.
  • Example 44 2-methyl-5- (2-nitrophenyl) thiophene-3-carboxylic acid methyl ester
  • the same reaction as in Reference Example 26 was carried out using 1-bromo-2-nitrobenzene instead of 2-chloro-6-fluorobenzaldehyde. And the title compound was obtained.
  • 1 H-NMR (CDCl 3 ) ⁇ (ppm): 2.77 (3H, s), 3.84 (3H, s), 7.37 (1H, s), 7.46-7.52 (2H, m), 7.55-7.61 (1H, m ), 7.79 (1H, dd, J 7.6Hz, 1.3Hz).
  • Example 45 5- (2-aminophenyl) -2-methylthiophene-3-carboxylic acid methyl ester 2-methyl-5- (2-nitrophenyl) thiophene-3-carboxylic acid methyl ester (621 mg) with acetic acid (6.75 mL) It melt
  • reaction solution B Copper (I) chloride (31.0 mg) was suspended in acetic acid (1.00 mL), an aqueous sulfur dioxide solution (2.50 mL) was added, and the mixture was stirred at 0 ° C. for 30 min (reaction solution B). Reaction solution A was added dropwise to reaction solution B at 0 ° C., and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product (127 mg).
  • the obtained crude product (125 mg) was dissolved in thionyl chloride (3.00 mL), N, N-dimethylformamide (2.00 ⁇ L) was added, and the mixture was refluxed for 2 hours.
  • the reaction solution was concentrated under reduced pressure, dissolved in tetrahydrofuran (3.00 mL), and a solution of 2-methoxyethanamine (69.0 ⁇ L), triethylamine (168 ⁇ L) and dimethylaminopyridine (10.0 mg) in tetrahydrofuran (500 ⁇ L) was added dropwise at 0 ° C. And stirred at room temperature for 3 hours. Distilled water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • Example 47 N- (5-chlorothiazol-2-yl) -5- [2- (2-methoxyethylsulfamoyl) phenyl] -2-methylthiophene-3-carboxamide 5- [2- (2-methoxyethylsulfa) Moyl) phenyl] -2-methylthiophene-3-carboxylic acid methyl ester (101 mg) was dissolved in a mixed solvent of tetrahydrofuran (1.00 mL) and water (1.00 mL), and lithium hydroxide monohydrate (34.0 mg) was dissolved. In addition, the mixture was stirred at 60 ° C. for 17 hours.
  • Reference Example 40 3- (3-Bromo-2-nitrophenyl) -2-oxopropanoic acid ethyl ester potassium ethoxide (3.9 g) is suspended in a mixed solvent of ethanol (3.0 mL) and N, N-dimethylformamide (50 mL). Diethyl oxalate (9.4 mL) was added dropwise at 0 ° C. N, N-dimethylformamide (20 mL) of 3-bromo-2-nitrotoluene (5.0 g) was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 1 hour.
  • Example 48 2-methyl-5- [2-nitro-3- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] phenyl] thiophene-3-carboxylic acid methyl ester instead of 2-chloro-6-fluorobenzaldehyde , 2- (3-Bromo-2-nitrophenoxy) tetrahydro-2H-pyran was reacted in the same manner as in Reference Example 26 to obtain the title compound.
  • Example 49 2-Methyl-5- [2-nitro-3- [3- (tetrahydro-2H-pyran-2-yloxy) propyl] phenyl] thiophene-3-carboxylic acid methyl ester 2- (3-bromo-2-nitrophene Tox) Instead of tetrahydro-2H-pyran, 2- [3- (3-bromo-2-nitrophenyl) propoxy] tetrahydro-2H-pyran was reacted in the same manner as in Example 48, and the title compound Got. ESI / MS (m / z): 420 (M + H) + , 418 (MH) - .
  • Example 50 2-methyl-5- [2-nitro-3- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] phenyl] thiophene-3-carboxylate 2-methyl-5-[-nitro-3- [ 2- (Tetrahydro-2H-pyran-2-yloxy) ethyl] phenyl] thiophene-3-carboxylic acid methyl ester (463 mg) was dissolved in a mixed solvent of tetrahydrofuran (4.50 mL) and water (4.50 mL) to obtain lithium hydroxide. Monohydrate (144 mg) was added and stirred at 60 ° C. for 20 hours.
  • Example 51 2-methyl-5- [2-nitro-3- [3- (tetrahydro-2H-pyran-2-yloxy) propyl] phenyl] thiophene-3-carboxylate 2-methyl-5- [2-nitro-3- Instead of [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] phenyl] thiophene-3-carboxylic acid methyl ester, 2-methyl-5- [2-nitro-3- [3- (tetrahydro-2H -Pyran-2-yloxy) propyl] phenyl] thiophene-3-carboxylic acid methyl ester was used in the same manner as in Example 50 to obtain the title compound.
  • Example 52 5- [2-Amino-3- (2-hydroxyethyl) phenyl] -N- (5-chlorothiazol-2-yl) -2-methylthiophene-3-carboxamide N- (5-chlorothiazol -2-yl) ) -2-Methyl-5- [2-nitro-3- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] phenyl] thiophene-3-carboxamide (320 mg) with acetic acid (3.40 mL) and water ( 370 ⁇ L) was dissolved in a mixed solvent, iron powder (176 mg) was added, and the mixture was stirred at 60 ° C. for 2 hours.
  • Example 27 With reference to the method of Example 27, the compound was synthesized according to the following reaction formula. The synthesized compounds are shown in Table 21, and the data are shown in Table 22.
  • Example 60 5- [3- (2-methoxyethyl) -2-nitrophenyl] -2-methylthiophene-3-carboxylic acid methyl ester instead of 2-chloro-6-fluorobenzaldehyde 1-bromo-3- (2- Reaction was carried out in the same manner as in Reference Example 26 using methoxyethyl) -2-nitrobenzene to obtain the title compound.
  • Example 61 5- [3- (2-methoxyethyl) -2-nitrophenyl] -2-methylthiophene-3-carboxylic acid 2-methyl-5-[-nitro-3- [2- (tetrahydro-2H-pyran-2) Instead of -yloxy) ethyl] phenyl] thiophene-3-carboxylic acid methyl ester, 5- [3- (2-methoxyethyl) -2-nitrophenyl] -2-methylthiophene-3-carboxylic acid methyl ester was used. In the same manner as in Example 50, the title compound was obtained.
  • Example 62 5- [2-Amino-3- (2-methoxyethyl) phenyl] -N- (5-fluorothiazol-2-yl) -2-methylthiophene-3-carboxamide N- (5 -fluorothiazol - 2-yl) ) -5- [3- (2-methoxyethyl) -2-nitrophenyl] -2-methylthiophene-3-carboxamide (18 mg) was dissolved in acetic acid (260 ⁇ L) and water (30 ⁇ L), and iron powder (14 mg) And stirred at 65 ° C. for 3 hours.
  • Example 63 5- [2-Amino-3- (2-methoxyethyl) phenyl] -N- (5-chlorothiazol-2-yl) -2-methylthiophene-3-carboxamide N- (5 -fluorothiazol - 2-yl) ) -5- [3- (2-methoxyethyl) -2-nitrophenyl] -2-methylthiophene-3-carboxamide instead of N- (5-chlorothiazol-2-yl) -5- [3- (2-Methoxyethyl) -2-nitrophenyl] -2-methylthiophene-3-carboxamide was used in the same manner as in Example 62 to obtain the title compound.
  • Example 64 2-methyl-5- [2-nitro-3- [2- (pivaloyloxy) ethyl] phenyl] thiophene-3-carboxylic acid methyl ester instead of 2-chloro-6-fluorobenzaldehyde 3-bromo-2-nitro Reaction was carried out in the same manner as in Reference Example 26 using phenethyl pivalate to obtain the title compound.
  • Example 65 Instead of 2-methyl-5- [2-nitro-3- [3- (pivaloyloxy) propyl] phenyl] thiophene-3-carboxylic acid methyl ester 3-bromo-2-nitrophenethylpivalate, 3- (3- Reaction was carried out in the same manner as in Example 64 using bromo-2-nitrophenyl) propyl pivalate to obtain the title compound.
  • Example 66 5- [2-Amino-3- [2- (pivaloyloxy) ethyl] phenyl] -2-methylthiophene-3-carboxylic acid methyl ester 2-methyl-5- [2-nitro-3- [2- (pivaloyloxy)] Ethyl] phenyl] thiophene-3-carboxylic acid methyl ester (3.38 g) is dissolved in a mixed solvent of ethanol (25.0 mL) and tetrahydrofuran (25.0 mL), 10% palladium on carbon (340 mg) is added, and hydrogen atmosphere is added at room temperature. For 17 hours. The reaction solution was filtered and washed with ethyl acetate.
  • Example 67 5- [2-Amino-3- [3- (pivaloyloxy) propyl] phenyl] -2-methylthiophene-3-carboxylic acid methyl ester 2-methyl-5- [2-nitro-3- [2- (pivaloyloxy) Instead of ethyl] phenyl] thiophene-3-carboxylic acid methyl ester, using 2-methyl-5- [2-nitro-3- [3- (pivaloyloxy) propyl] phenyl] thiophene-3-carboxylic acid methyl ester Reaction was carried out in the same manner as in Example 66 to obtain the title compound.
  • Example 68 5- [2-Cyano-3- [2- (pivaloyloxy) ethyl] phenyl] -2-methylthiophene-3-carboxylic acid methyl ester 5- [2-amino-3- [2- (pivaloyloxy) ethyl] phenyl] -2-Methylthiophene-3-carboxylic acid methyl ester (1.06 g) was dissolved in a mixed solvent of 1,4-dioxane (4.00 mL) and water (1.50 mL), hydrochloric acid (2.00 mL) was added at 0 ° C., and Further, a solution of sodium nitrite (330 mg) in water (1.00 mL) was added dropwise, and the mixture was stirred at 0 ° C.
  • Potassium cyanide (881 mg) and copper (I) cyanide (959 mg) are suspended in a mixed solvent of 1,4-dioxane (5.00 mL) and water (5.00 mL), and the reaction solution A is added dropwise at 0 ° C. Stir for hours.
  • Water and ethyl acetate were added to the reaction solution, filtered, and washed with ethyl acetate. The filtrate was separated, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure.
  • Example 69 5- [2-Cyano-3- [3- (pivaloyloxy) propyl] phenyl] -2-methylthiophene-3-carboxylic acid methyl ester 5- [2-amino-3- [2- (pivaloyloxy) ethyl] phenyl] Instead of 2-methylthiophene-3-carboxylic acid methyl ester, using 5- [2-amino-3- [3- (pivaloyloxy) propyl] phenyl] -2-methylthiophene-3-carboxylic acid methyl ester Reaction was carried out in the same manner as in Example 68 to obtain the title compound.
  • Example 70 5- [2-carbamoyl-3- [2- (pivaloyloxy) ethyl] phenyl] -2-methylthiophene-3-carboxylic acid methyl ester 5- [2-cyano-3- [2- (pivaloyloxy) ethyl] phenyl] -2-Methylthiophene-3-carboxylic acid methyl ester (3.89 g) is dissolved in a mixed solvent of ethanol (38.5 mL) and water (19.3 mL), and is designated as IIa in Tetrahedron Letters, 1995, 36, 8657-8660. The described platinum catalyst (127 mg) was added and stirred at 90 ° C. for 16 hours.
  • Example 71 5- [2-carbamoyl-3- [3- (pivaloyloxy) propyl] phenyl] -2-methylthiophene-3-carboxylic acid methyl ester 5- [2-cyano-3- [2- (pivaloyloxy) ethyl] phenyl] Instead of 2-methylthiophene-3-carboxylic acid methyl ester, using 5- [2-cyano-3- [3- (pivaloyloxy) propyl] phenyl] -2-methylthiophene-3-carboxylic acid methyl ester Reaction was carried out in the same manner as in Example 70 to obtain the title compound.
  • reaction solution A Copper (I) chloride (603 mg) was suspended in acetic acid (15 mL), an aqueous sulfur dioxide solution (29.0 mL) was added, and the mixture was stirred at 0 ° C. for 30 min. The reaction liquid A was dripped at 0 degreeC, and it stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure.
  • Example 72 2-methyl-5- [2-methylsulfonyl-3- [2- (pivaloyloxy) ethyl] phenyl] thiophene-3-carboxylic acid methyl ester sodium sulfite (2.27 g) and sodium hydrogen carbonate (1.51 g) were added to water (38.0 5- [2-chlorosulfonyl-3- [2- (pivaloyloxy) ethyl] phenyl] -2-methylthiophene-3-carboxylic acid methyl ester (3.88 g) 1,4-dioxane (76.0 mL) The solution was added dropwise and stirred at 70 ° C. for 2 hours.
  • Example 73 2-Methyl-5- [2-methylsulfonyl-3- [3- (pivaloyloxy) propyl] phenyl] thiophene-3-carboxylic acid methyl ester 5- [2-chlorosulfonyl-3- [2- (pivaloyloxy) ethyl] Instead of phenyl] -2-methylthiophene-3-carboxylic acid methyl ester, 5- [2-chlorosulfonyl-3- [3- (pivaloyloxy) propyl] phenyl] -2-methylthiophene-3-carboxylic acid methyl ester was used in the same manner as in Example 72 to obtain the title compound.
  • Example 75 5- [2-acetyl-3- [3- (pivaloyloxy) propyl] phenyl] -2-methylthiophene-3-carboxylic acid methyl ester instead of 2-chloro-6-fluorobenzaldehyde 3- [2-acetyl- The title compound was obtained in the same manner as in Reference Example 26 using 3- (trifluoromethylsulfonyloxy) phenyl] propyl pivalate.
  • Example 76 5- [2-carbamoyl-3- (2-hydroxyethyl) phenyl] -2-methylthiophene-3-carboxylic acid 5- [2-carbamoyl-3- [2- (pivaloyloxy) ethyl] phenyl] -2-methyl Thiophene-3-carboxylic acid methyl ester (3.83 g) is dissolved in a mixed solvent of tetrahydrofuran (38.0 mL) and water (38.0 mL), lithium hydroxide monohydrate (1.19 g) is added, and the mixture is heated at 60 ° C. for 17 hours. Stir.
  • the compound was synthesized according to the following reaction formula with reference to the method of Example 76.
  • the synthesized compounds are shown in Table 23 and the data are shown in Table 24.
  • Example 81 5- [2-carbamoyl-3- (2-hydroxyethyl) phenyl] -N- (5-fluorothiazol-2-yl) -2-methylthiophene-3-carboxamide 5- [2-carbamoyl-3- (2 -Hydroxyethyl) phenyl] -2-methylthiophene-3-carboxylic acid (150 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (188 mg) and 1-hydroxy-1H-benzotriazole monohydrate (150 mg), diisopropylamine (257 ⁇ L) and 2-amino-5-fluorothiazole hydrochloride (228 mg) were dissolved in N, N-dimethylformamide (3.00 mL), stirred at room temperature for 2 hours, and further at 60 ° C.
  • Example 81 With reference to the method of Example 81, the compound was synthesized according to the following reaction formula. The synthesized compounds are shown in Table 25 and the data are shown in Table 26.
  • Example 98 With reference to the method of Example 98, the compound was synthesized according to the following reaction formula. The synthesized compounds are shown in Table 27 and the data are shown in Table 28.
  • Example 103 With reference to the method of Example 103, the compound was synthesized according to the following reaction formula. The synthesized compounds are shown in Table 31 and the data are shown in Table 32.
  • Pharmacological test example 1 Expression and purification of human glucokinase DNA fragment with the same restriction enzyme site added to the N-terminal deletion (1-15 amino acid deletion) coding region of human GK at EcoRI and HindIII sites of pQE-80 expression vector did. E. coli was transformed with this plasmid to express human glucokinase and purified as follows. The cells recovered from the 200 ml E. coli culture solution are collected and suspended in 20 ml of Extraction buffer A (20 mM HEPES, pH 8.0, 1 mM MgCl2, 150 mM NaCl, 2 mM mercaptoethanol, 0.25 mg / ml lysozyme, 50 mg / ml sodium azide).
  • Extraction buffer A (20 mM HEPES, pH 8.0, 1 mM MgCl2, 150 mM NaCl, 2 mM mercaptoethanol, 0.25 mg / ml lysozyme, 50 mg /
  • Extraction buffer B 1.5 M NaCl, 100 mM CaCl 2, 100 mM MgCl 2, 0.02 mg / ml DNA-degrading enzyme 1, protease inhibitor tablet (Complete (registered trademark) 1697498): one tablet per 20 ml of buffer
  • the extract was centrifuged at 15,000 g for 30 minutes at 4 ° C., and the supernatant was used as an E. coli extract.
  • coli extract was filtered through a 0.45 ⁇ m filter and applied to Ni-NTAagarose 2 mLbed equilibrated with a buffer containing 20 mM imidazole (20 mM HEPES pH 8.0, 0.5 M NaCl). It was washed with about 10 ml of washing buffer and eluted stepwise with a buffer containing 20 to 500 mM imidazole (20 mM HEPES pH 8.0, 0.5 M NaCl). Each column fraction was analyzed using SDS gel electrophoresis, and the fraction containing hGK (MW: 52 KDa) was concentrated.
  • the concentrated sample was passed through a Sephacryl S-200HR (11/60) gel filtration column and eluted with buffer B (20 mM HEPES, pH 8.0, 1 mM MgCl 2, 150 mM NaCl, 1 mM DTT).
  • buffer B (20 mM HEPES, pH 8.0, 1 mM MgCl 2, 150 mM NaCl, 1 mM DTT).
  • the eluted fraction was analyzed by SDS gel electrophoresis, and the fraction containing hGK was concentrated. Finally, 50% glycerol was added and stored at -20 ° C.
  • the compound of the present invention Since the compound of the present invention has a glucokinase activating action, it is a chronic complication of diabetes such as diabetes or diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, ischemic heart disease, or arteriosclerosis. It is useful as a preventive or therapeutic agent.

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Abstract

La présente invention concerne des composés qui possèdent un effet d'activation de la glucokinase. L'invention concerne également des compositions pharmaceutiques qui contiennent chacune un composé représenté par la formule (I) générale ou l'un de ses sels pharmacologiquement acceptables en tant que principe actif. Dans la formule générale (I), X représente un atome d'azote ou CR2, R2 représentant un atome d'halogène, un groupe alkyle en C1 à C6, ou analogues ; Y représente un atome d'azote ou CR3, R3 représentant un atome d'hydrogène, un groupe alkyle en C1 à C6, ou analogues, à condition que lorsque X représente un atome d'azote, Y ne représente pas un atome d'azote ; Z représente un atome d'azote ou CR4, R4 représentant un atome d'hydrogène, un atome d'halogène ou un groupe (CH2)m-R5 [où m représente un nombre entier de 1 à 6 et R5 représente un groupe hydroxyle ou analogues] ; et R1 représente un groupe amino, mésyle, carbamoyle, CONH-(CH2)n-A-R6 [où n représente un nombre entier de 1 à 6, A est nul, un atome d'oxygène ou analogues, et R6 représente un groupe alkyle en C1 à C6, hydroxyalkyle en C1 à C6, ou analogues], ou analogues.
PCT/JP2011/064183 2010-06-22 2011-06-21 Nouveaux dérivés de thiophène-carboxamide et leur utilisation en tant que médicament WO2011162267A1 (fr)

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WO2018177993A1 (fr) 2017-03-31 2018-10-04 Bayer Cropscience Aktiengesellschaft Pyrazoles pour lutter contre les arthropodes
WO2020017878A1 (fr) * 2018-07-20 2020-01-23 Hexapharmatec Co., Ltd. Nouveaux dérivés de catéchol ou sel de ceux-ci, leurs procédés de préparation et compositions pharmaceutiques les comprenant
CN113444081A (zh) * 2021-07-30 2021-09-28 浙江大学 噻二唑酰胺类化合物及其应用
WO2022255499A1 (fr) * 2021-06-04 2022-12-08 学校法人京都薬科大学 Nouvel activateur de protéine kinase activée par l'amp
RU2795227C2 (ru) * 2018-07-20 2023-05-02 Хексафарматэк Ко., Лтд. Новые производные катехола или их соль, способы их получения и содержащие их фармацевтические композиции

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WO2009106203A1 (fr) * 2008-02-25 2009-09-03 Merck Patent Gmbh Activateurs de la glucokinase
WO2010150899A1 (fr) * 2009-06-26 2010-12-29 株式会社 三和化学研究所 Nouveau dérivé de carboxamide de thiophène et son utilisation médicale

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SU385969A1 (ru) * 1971-04-02 1973-06-14 Авторы изобретени Способ получения производных
WO2009106203A1 (fr) * 2008-02-25 2009-09-03 Merck Patent Gmbh Activateurs de la glucokinase
WO2010150899A1 (fr) * 2009-06-26 2010-12-29 株式会社 三和化学研究所 Nouveau dérivé de carboxamide de thiophène et son utilisation médicale

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018177993A1 (fr) 2017-03-31 2018-10-04 Bayer Cropscience Aktiengesellschaft Pyrazoles pour lutter contre les arthropodes
WO2020017878A1 (fr) * 2018-07-20 2020-01-23 Hexapharmatec Co., Ltd. Nouveaux dérivés de catéchol ou sel de ceux-ci, leurs procédés de préparation et compositions pharmaceutiques les comprenant
CN112437773A (zh) * 2018-07-20 2021-03-02 六合医药科技有限公司 新的儿茶酚衍生物或其盐，其制备方法以及包含其的药物组合物
RU2795227C2 (ru) * 2018-07-20 2023-05-02 Хексафарматэк Ко., Лтд. Новые производные катехола или их соль, способы их получения и содержащие их фармацевтические композиции
CN112437773B (zh) * 2018-07-20 2024-06-11 六合医药科技有限公司 新的儿茶酚衍生物或其盐，其制备方法以及包含其的药物组合物
WO2022255499A1 (fr) * 2021-06-04 2022-12-08 学校法人京都薬科大学 Nouvel activateur de protéine kinase activée par l'amp
CN113444081A (zh) * 2021-07-30 2021-09-28 浙江大学 噻二唑酰胺类化合物及其应用
WO2023004897A1 (fr) * 2021-07-30 2023-02-02 浙江大学 Composé thiadiazole amide et son utilisation

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