WO2013018675A1 - N-ヘテロ環置換アミド誘導体 - Google Patents
N-ヘテロ環置換アミド誘導体 Download PDFInfo
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- WO2013018675A1 WO2013018675A1 PCT/JP2012/069098 JP2012069098W WO2013018675A1 WO 2013018675 A1 WO2013018675 A1 WO 2013018675A1 JP 2012069098 W JP2012069098 W JP 2012069098W WO 2013018675 A1 WO2013018675 A1 WO 2013018675A1
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- mmol
- cyclopropylcarbonyl
- phenoxy
- oxadiazol
- fluoro
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—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
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
Definitions
- the present invention relates to a novel N-heterocyclic substituted amide derivative having a hypoglycemic action and / or a beta cell or pancreas protecting action, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing these as active ingredients. .
- Diabetes is a metabolic disease mainly characterized by chronic hyperglycemia due to insufficient insulin action.
- drug therapy is generally administered together with diet therapy and exercise therapy.
- Oral hypoglycemic agents that are a type of anti-diabetic agent include biguanides or thiazolidinediones that improve insulin resistance, sulfonylureas or glinides that promote insulin secretion from pancreatic ⁇ cells, and ⁇ that inhibit sugar absorption -Glucosidase inhibitors are used.
- Patent Documents 1 to 4 have a problem that it is difficult to obtain a sufficient hypoglycemic action and ⁇ -cell or pancreas protective action.
- the above Patent Documents 1 to 6 do not describe or suggest the present invention. Therefore, the present invention has a new structure not described or suggested in the above-mentioned patent document, and has an excellent hypoglycemic action, ⁇ -cell or pancreas protective action, or a pharmaceutically acceptable substance thereof.
- a pharmaceutical composition having an excellent therapeutic effect and / or preventive effect on type 1 diabetes, type 2 diabetes and the like that cause an increase in blood sugar due to abnormalities of salt and sugar metabolism, and a pharmaceutical composition having a ⁇ -cell or pancreatic protective action The purpose is to provide.
- R 2 is a methyl group or an ethyl group
- R 2 is a methyl group or an ethyl group
- a pharmaceutically acceptable salt thereof (2) The following: 4- (5- ⁇ (1R) -1- [4- (cyclopropylcarbonyl) phenoxy] propyl ⁇ -1,2,4-oxadiazol-3-yl) -2-fluoro-N-[(3S, 4R) -4-hydroxytetrahydrofuran-3-yl] benzamide; 4- (5- ⁇ (1R) -1- [4- (cyclopropylcarbonyl) phenoxy] propyl ⁇ -1,2,4-oxadiazol-3-yl) -2-fluoro-N-[(3R, 4S) -4-hydroxytetrahydrofuran-3-yl] benzamide; 4- (5- ⁇ (1R) -1- [4- (cyclopropylcarbonyl) phenoxy] ethyl ⁇ -1,2,4
- an N-heterocyclic substituted amide derivative or a pharmaceutically acceptable salt thereof having an excellent hypoglycemic action and ⁇ -cell or pancreas protective action, type 1 diabetes, type 2 diabetes, etc. It is possible to provide a pharmaceutical composition having an excellent therapeutic effect and / or preventive effect, and a pharmaceutical composition having a ⁇ -cell or pancreas protective effect.
- the “pharmaceutically acceptable salt” refers to a salt formed by reacting the compound of the present invention with an acid or a base.
- the salt examples include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide; hydrochloride, nitrate, perchlorate, sulfate, phosphate, etc.
- Inorganic acid salts lower alkane sulfonates such as methane sulfonate, trifluoromethane sulfonate and ethane sulfonate; aryl sulfonates such as benzene sulfonate and p-toluene sulfonate; acetate, malic acid Organic salts such as salts, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate; alkali metal salts such as sodium, potassium and lithium; calcium salt , Alkaline earth metal salts such as magnesium salts; metal salts such as aluminum salts and iron salts; inorganic salts such as ammonium salts; t-octy
- the compound of the present invention When the compound of the present invention is left, for example, in the atmosphere, it absorbs moisture and attaches adsorbed water to form a hydrate. Such a hydrate is also included in the salt of the present invention. Is done.
- the present invention includes all optical isomers of the compound represented by the general formula (I) and mixtures in arbitrary ratios of the optical isomers.
- Such optical isomers can be produced, for example, using raw materials having optical activity instead of the raw materials in the production methods, reference examples and examples described later, and the production methods, reference examples and examples described later.
- the compound produced with reference to the above can also be obtained by using an optical resolution method known in the art, for example, a diastereomer method, an enzyme reaction method, an optical resolution method by chromatography, and the like.
- the present invention can also include a compound in which one or more atoms constituting the compound represented by the general formula (I) are substituted with an isotope of the atom.
- isotopes There are two types of isotopes: radioactive isotopes and stable isotopes. Examples of isotopes include hydrogen isotopes ( 2 H and 3 H), carbon isotopes ( 11 C, 13 C and 14 C), nitrogen isotopes ( 13 N and 15 N), oxygen isotopes ( 15 O, 17 O and 18 O), fluorine isotopes ( 18 F) and the like.
- a composition containing a compound labeled with an isotope is useful, for example, as a therapeutic agent, prophylactic agent, research reagent, assay reagent, diagnostic agent, in vivo diagnostic imaging agent, and the like. All isotope-labeled compounds and mixtures of isotope-labeled compounds in any proportion are also encompassed by the invention.
- An isotope-labeled compound can be produced by a method known in the art, for example, by using a raw material labeled with an isotope instead of the raw material in the production method of the present invention described later.
- the present invention can also include a prodrug of the compound represented by the general formula (I).
- a prodrug is a derivative of a compound represented by the general formula (I), and refers to a compound that is enzymatically or chemically converted into the compound of the present invention in vivo.
- Prodrugs include compounds in which the amino group in the molecule is acylated, alkylated or phosphorylated, compounds in which the carboxyl group in the molecule is esterified or amidated, and hydroxy groups in the molecule are acylated, alkylated or Examples include phosphorylated compounds (see, for example, Povl Krogsgaard-Larsen et al., “A Textbook of Drug Design and Development”, second edition, harwood academic publishers, 1996, pages 351-385). Such a prodrug can be produced from the compound represented by the general formula (I) by a method known in the art.
- the compound of the present invention can be easily produced from a known compound according to Reference Examples and Examples described later.
- the compound of the present invention obtained by the above method or a pharmaceutically acceptable salt thereof has an excellent hypoglycemic action, type 1 diabetes, type 2 diabetes, gestational diabetes, other factors, hyperglycemia, glucose tolerance Impaired (glucose) tolerance (IGT), obesity, diabetes-related diseases (eg, hyperlipidemia, hypercholesterolemia, dyslipidemia, hypertension, fatty liver, metabolic syndrome, edema, heart failure, angina, myocardial infarction , Arteriosclerosis, hyperuricemia, gout, etc.) or diabetic complications (eg retinopathy, nephropathy, neuropathy, cataract, foot gangrene, infection, ketosis, etc.) It can be used as an active ingredient of a pharmaceutical composition.
- diabetes-related diseases eg, hyperlipidemia, hypercholesterolemia, dyslipidemia, hypertension, fatty liver, metabolic syndrome, edema, heart failure, angina, myocardial infarction , Arteriosclerosis, hyperuricemia,
- the compound of the present invention or a pharmaceutically acceptable salt thereof since the compound of the present invention or a pharmaceutically acceptable salt thereof has an excellent ⁇ -cell or pancreas protective action, it is used as an active ingredient in a pharmaceutical composition that can be used to protect ⁇ -cells or pancreas. obtain.
- the compound of the present invention can also be used in combination with a therapeutic drug for diabetes, a therapeutic drug for diabetic complications, a therapeutic drug for hyperlipidemia, a therapeutic drug for hypertension and the like other than the compound of the present invention.
- a pharmaceutical composition containing a compound of the present invention or a pharmaceutically acceptable salt thereof is systemically or when administered to a mammal (eg, human, horse, cow, pig, etc., preferably human). It can be administered topically, orally or parenterally.
- a mammal eg, human, horse, cow, pig, etc., preferably human. It can be administered topically, orally or parenterally.
- the pharmaceutical composition of the present invention can be prepared by selecting an appropriate form according to the administration method and preparing various preparations usually used.
- oral pharmaceutical composition examples include tablets, pills, powders, granules, capsules, solutions, suspensions, emulsions, syrups, elixirs and the like.
- the pharmaceutical composition in such a form comprises excipients, binders, disintegrants, lubricants, swelling agents, swelling aids, coating agents, plasticizers, stabilizers, preservatives, antioxidants that are usually used as additives.
- Coloring agents, solubilizers, suspending agents, emulsifiers, sweeteners, preservatives, buffers, diluents, wetting agents, and the like may be appropriately selected as necessary and produced according to conventional methods.
- parenteral pharmaceutical composition examples include injections, ointments, gels, creams, poultices, patches, sprays, inhalants, sprays, eye drops, nasal drops, suppositories, and the like.
- the pharmaceutical composition in such a form includes stabilizers, preservatives, solubilizers, moisturizers, preservatives, antioxidants, flavoring agents, gelling agents, neutralizing agents, buffering agents, which are usually used as additives. Isotonic agents, surfactants, colorants, buffering agents, thickeners, wetting agents, fillers, absorption enhancers, suspending agents, binders, etc. are appropriately selected as necessary and manufactured according to conventional methods. Can be done.
- the dose of the compound of the present invention or a pharmaceutically acceptable salt thereof varies depending on symptoms, age, body weight, etc. In the case of oral administration, it is 1 to several times a day, once per adult, as a compound.
- the amount is 1 to 2000 mg, preferably 1 to 400 mg, and in the case of parenteral administration, the amount is 0.01 to 500 mg, preferably 0.1 to 300 mg in terms of compound per adult once or several times a day.
- Trifluoroacetic acid (10 mL) was added to a solution of the compound obtained in Reference Example 7 (236 mg, 0.506 mmol) in dichloromethane (1 mL) at room temperature and stirred for 40 minutes. The solvent was distilled off under reduced pressure, and the resulting residue was washed with isopropyl ether to obtain the title compound (195 mg, 94%).
- Example 1 4- (5- ⁇ (1R) -1- [4- (cyclopropylcarbonyl) phenoxy] propyl ⁇ -1,2,4-oxadiazol-3-yl) -2-fluoro-N -[(3S, 4R) -4-hydroxytetrahydrofuran-3-yl] benzamide and 4- (5- ⁇ (1R) -1- [4- (cyclopropylcarbonyl) phenoxy] propyl ⁇ -1,2, 4-oxadiazol-3-yl) -2-fluoro-N-[(3R, 4S) -4-hydroxytetrahydrofuran-3-yl] benzamide
- Example 2 4- (5- ⁇ (1R) -1- [4- (cyclopropylcarbonyl) phenoxy] ethyl ⁇ -1,2,4-oxadiazol-3-yl) -2-fluoro-N -[(3R, 4S) -4-Hydroxytetrahydrofuran-3-yl] benzamide
- Example 3 4- (5- ⁇ (1R) -1- [4- (cyclopropylcarbonyl) phenoxy] ethyl ⁇ -1,2,4-oxadiazol-3-yl) -2-fluoro-N -[(3S, 4R) -4-Hydroxytetrahydrofuran-3-yl] benzamide
- Example 4 4- (5- ⁇ (1R) -1- [4- (cyclopropylcarbonyl) phenoxy] propyl ⁇ -1,2,4-oxadiazol-3-yl) -2-fluoro-N -[(3R) -2-Oxotetrahydrofuran-3-yl] benzamide
- Example 5 4- (5- ⁇ (1R) -1- [4- (cyclopropylcarbonyl) phenoxy] propyl ⁇ -1,2,4-oxadiazol-3-yl) -2-fluoro-N -[(3S) -2-Oxotetrahydrofuran-3-yl] benzamide
- Example 6 4- (5- ⁇ (1R) -1- [4- (cyclopropylcarbonyl) phenoxy] propyl ⁇ -1,2,4-oxadiazol-3-yl) -2-fluoro-N -[(3S) -5-Oxotetrahydrofuran-3-yl] benzamide
- Example 7 4- (5- ⁇ (1R) -1- [4- (cyclopropylcarbonyl) phenoxy] propyl ⁇ -1,2,4-oxadiazol-3-yl) -2-fluoro-N -[(3R) -2-Oxopyrrolidin-3-yl] benzamide
- Example 8 4- (5- ⁇ (1R) -1- [4- (cyclopropylcarbonyl) phenoxy] propyl ⁇ -1,2,4-oxadiazol-3-yl) -2-fluoro-N -[(3S) -2-Oxopyrrolidin-3-yl] benzamide
- Example 9 4- (5- ⁇ (1R) -1- [4- (cyclopropylcarbonyl) phenoxy] propyl ⁇ -1,2,4-oxadiazol-3-yl) -2-fluoro-N -[(3S, 4S) -4-Hydroxy-2-oxotetrahydrofuran-3-yl] benzamide
- Example 10 4- (5- ⁇ (1R) -1- [4- (cyclopropylcarbonyl) phenoxy] ethyl ⁇ -1,2,4-oxadiazol-3-yl) -2-fluoro-N -[(3R) -2-Oxopyrrolidin-3-yl] benzamide
- Example 11 4- (5- ⁇ (1R) -1- [4- (cyclopropylcarbonyl) phenoxy] ethyl ⁇ -1,2,4-oxadiazol-3-yl) -2-fluoro-N -[(3S) -2-Oxopyrrolidin-3-yl] benzamide
- Example 12 4- (5- ⁇ (1R) -1- [4- (cyclopropylcarbonyl) phenoxy] propyl ⁇ -1,2,4-oxadiazol-3-yl) -2-fluoro-N -[(3S, 4R) -4-Hydroxy-2-oxotetrahydrofuran-3-yl] benzamide
- Example 13 4- (5- ⁇ (1R) -1- [4- (cyclopropylcarbonyl) phenoxy] ethyl ⁇ -1,2,4-oxadiazol-3-yl) -2-fluoro-N -[(3R, 4R) -4-Hydroxytetrahydrofuran-3-yl] benzamide
- Example 14 4- (5- ⁇ (1R) -1- [4- (cyclopropylcarbonyl) phenoxy] ethyl ⁇ -1,2,4-oxadiazol-3-yl) -2-fluoro-N -[(3S, 4S) -4-Hydroxytetrahydrofuran-3-yl] benzamide
- a compound is obtained by mixing 5 g of the compound obtained in Examples, 90 g of lactose, 34 g of corn starch, 20 g of crystalline cellulose and 1 g of magnesium stearate with a blender, and then tableting with a tableting machine.
- mice Animal oGTT (oral glucose tolerance test) test
- the compound administration solution is a 0.5 w / v% methylcellulose solution, and a suspension is prepared so as to have a concentration of 1 mg / mL while being pulverized in an agate mortar. did.
- Animals received male C57 / BL6J mice (Nippon Charles River Co., Ltd.) from 6 to 8 weeks of age and used from 9 to 13 weeks of age. Fasting was started between 17:00 and 18:00 the day before the test day, and the test was started under fasting for about 16 to 17 hours. Five animals were used in each group. After blood was collected from the tail vein, the compound suspension was orally administered at 10 mg / kg.
- a 0.5 w / v% methylcellulose solution was administered to the negative control group.
- Blood was collected from the tail vein 25 minutes after oral administration, and 30 w / v% glucose solution was orally administered at 10 mL / kg 30 minutes after oral administration.
- Blood was collected from the tail vein 15 minutes, 30 minutes, 60 minutes, and 120 minutes after the glucose load.
- the collected blood was centrifuged to separate the plasma, and plasma blood glucose level (mg / dL) was measured with Glucoroder-GXT (A & T).
- AUC (mg / dL ⁇ min) was calculated using the blood glucose level 5 minutes before glucose load, 15 minutes, 30, 60 minutes, and 120 minutes after glucose load.
- the AUC average value for each group was calculated, and the AUC reduction rate (%) compared with the negative control group was calculated as an index of drug efficacy.
- the compounds of Examples 3, 8, 10, and 13 showed an AUC reduction rate of 5% or more and less than 15%, and the compounds of Examples 1, 2, 4 to 7, 9, 11, 12, and 14 were 15%.
- the above AUC reduction rate was shown.
- the compound administration solution prepared by the above-mentioned method is orally administered to the rat at 1 to 5 mL / kg, and 30 to 30 minutes later, the 25 to 50 w / v% glucose solution is orally administered at 4 mL / kg.
- Blood is collected from the rat tail vein before compound administration, 5 minutes before glucose administration, and 30, 60, 120 and 180 minutes after glucose administration. After the obtained blood is centrifuged, the plasma is separated and the plasma blood glucose level is measured with Glucoroder-GXT (A & T). The AUC of the blood glucose level after glucose administration in each group is calculated, and the reduction rate (%) with respect to the blood glucose level AUC in the vehicle administration group is expressed as the efficacy of the compound.
- the plasma obtained by the above method is used for measuring the blood concentration of the test compound.
- blood is also collected from 4 to 8 hours and 24 hours after administration.
- the concentration of the compound in the blood is calculated using a liquid chromatography / mass spectrometer.
- the compound of the present invention or a pharmaceutically acceptable salt thereof treats and / or treats type 1 diabetes, type 2 diabetes, gestational diabetes, hyperglycemia due to other factors, glucose intolerance, diabetes related diseases, diabetic complications and the like. Or, for prevention, it is useful as an active ingredient of a pharmaceutical composition for protecting ⁇ cells or pancreas.
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Abstract
Description
(1)一般式(I):
R1は、
*は、窒素原子との結合位置であり、
R2は、メチル基またはエチル基である)
で表される化合物またはその薬学的に許容され得る塩;
(2)以下:
4-(5-{(1R)-1-[4-(シクロプロピルカルボニル)フェノキシ]プロピル}-1,2,4-オキサジアゾール-3-イル)-2-フルオロ-N-[(3S,4R)-4-ヒドロキシテトラヒドロフラン-3-イル]ベンズアミド;
4-(5-{(1R)-1-[4-(シクロプロピルカルボニル)フェノキシ]プロピル}-1,2,4-オキサジアゾール-3-イル)-2-フルオロ-N-[(3R,4S)-4-ヒドロキシテトラヒドロフラン-3-イル]ベンズアミド;
4-(5-{(1R)-1-[4-(シクロプロピルカルボニル)フェノキシ]エチル}-1,2,4-オキサジアゾール-3-イル)-2-フルオロ-N-[(3R,4S)-4-ヒドロキシテトラヒドロフラン-3-イル]ベンズアミド;
4-(5-{(1R)-1-[4-(シクロプロピルカルボニル)フェノキシ]エチル}-1,2,4-オキサジアゾール-3-イル)-2-フルオロ-N-[(3S,4R)-4-ヒドロキシテトラヒドロフラン-3-イル]ベンズアミド;
4-(5-{(1R)-1-[4-(シクロプロピルカルボニル)フェノキシ]プロピル}-1,2,4-オキサジアゾール-3-イル)-2-フルオロ-N-[(3R)-2-オキソテトラヒドロフラン-3-イル]ベンズアミド;
4-(5-{(1R)-1-[4-(シクロプロピルカルボニル)フェノキシ]プロピル}-1,2,4-オキサジアゾール-3-イル)-2-フルオロ-N-[(3S)-2-オキソテトラヒドロフラン-3-イル]ベンズアミド;
4-(5-{(1R)-1-[4-(シクロプロピルカルボニル)フェノキシ]プロピル}-1,2,4-オキサジアゾール-3-イル)-2-フルオロ-N-[(3S)-5-オキソテトラヒドロフラン-3-イル]ベンズアミド;
4-(5-{(1R)-1-[4-(シクロプロピルカルボニル)フェノキシ]プロピル}-1,2,4-オキサジアゾール-3-イル)-2-フルオロ-N-[(3R)-2-オキソピロリジン-3-イル]ベンズアミド;
4-(5-{(1R)-1-[4-(シクロプロピルカルボニル)フェノキシ]プロピル}-1,2,4-オキサジアゾール-3-イル)-2-フルオロ-N-[(3S)-2-オキソピロリジン-3-イル]ベンズアミド;
4-(5-{(1R)-1-[4-(シクロプロピルカルボニル)フェノキシ]プロピル}-1,2,4-オキサジアゾール-3-イル)-2-フルオロ-N-[(3S,4S)-4-ヒドロキシ-2-オキソテトラヒドロフラン-3-イル]ベンズアミド;
4-(5-{(1R)-1-[4-(シクロプロピルカルボニル)フェノキシ]エチル}-1,2,4-オキサジアゾール-3-イル)-2-フルオロ-N-[(3R)-2-オキソピロリジン-3-イル]ベンズアミド;
4-(5-{(1R)-1-[4-(シクロプロピルカルボニル)フェノキシ]エチル}-1,2,4-オキサジアゾール-3-イル)-2-フルオロ-N-[(3S)-2-オキソピロリジン-3-イル]ベンズアミド;
4-(5-{(1R)-1-[4-(シクロプロピルカルボニル)フェノキシ]プロピル}-1,2,4-オキサジアゾール-3-イル)-2-フルオロ-N-[(3S,4R)-4-ヒドロキシ-2-オキソテトラヒドロフラン-3-イル]ベンズアミド;
4-(5-{(1R)-1-[4-(シクロプロピルカルボニル)フェノキシ]エチル}-1,2,4-オキサジアゾール-3-イル)-2-フルオロ-N-[(3R,4R)-4-ヒドロキシテトラヒドロフラン-3-イル]ベンズアミド;および
4-(5-{(1R)-1-[4-(シクロプロピルカルボニル)フェノキシ]エチル}-1,2,4-オキサジアゾール-3-イル)-2-フルオロ-N-[(3S,4S)-4-ヒドロキシテトラヒドロフラン-3-イル]ベンズアミド;
からなる群より選択される化合物またはその薬学的に許容され得る塩;
(3)前記(1)または(2)に記載の化合物またはその薬学的に許容され得る塩を有効成分として含有する医薬組成物;
(4)1型糖尿病、2型糖尿病または肥満を治療するための、前記(3)に記載の医薬組成物;
(5)β細胞または膵臓を保護するための、前記(3)に記載の医薬組成物;
(6)医薬組成物を製造するための、前記(1)または(2)に記載の化合物またはその薬学的に許容され得る塩の使用;
(7)医薬組成物が1型糖尿病、2型糖尿病または肥満を治療するため、あるいは、β細胞または膵臓を保護するために用いられる、前記(6)に記載の使用;
(8)前記(1)または(2)に記載の化合物またはその薬学的に許容され得る塩を哺乳動物に投与することを含む、疾病を治療する方法;
(9)疾病が1型糖尿病、2型糖尿病または肥満である、前記(8)に記載の方法;
(10)前記(1)または(2)に記載の化合物またはその薬学的に許容され得る塩を哺乳動物に投与することを含む、β細胞または膵臓を保護する方法;ならびに、
(11)哺乳動物がヒトである前記(8)に記載の方法;
を提供する。
1H-NMR (400MHz, CDCl3)δppm:
7.89 (1H, t, J = 8 Hz), 7.44 (2H, dd, J = 8, 2 Hz), 7.39 (2H, dd, J = 11, 2 Hz), 4.90 (2H, s), 1.60 (9H, s).
1H-NMR (400MHz, CDCl3)δppm:
7.99-7.96 (2H, m), 6.93-6.89 (2H, m), 6.16 (1H, s), 2.67-2.61 (1H, m), 1.28-1.18 (2H, m), 1.09-0.97 (2H, m).
1H-NMR (400MHz, CDCl3)δppm:
5.00 (1H, m), 2.15 (3H, s), 1.94-1.90 (2H, m), 1.03 (3H, t, J = 7 Hz);
MS (FAB) m/z: 147 [M+H]+.
1H-NMR (400MHz, CDCl3) δppm:
7.96 (1H, t, J = 8 Hz), 7.90 (1H, dd, J = 8, 2 Hz), 7.84 (1H, dd, J = 11, 2 Hz), 5.92 (1H, t, J = 7 Hz), 2.21 (3H, s), 2.16-2.08 (2H, m), 1.62 (9H, s), 1.05 (3H, t, J = 7 Hz);
MS (FAB) m/z: 365 [M+H]+.
1H-NMR (400MHz, CDCl3) δppm:
7.97 (1H, t, J = 8 Hz), 7.91 (1H, d, J = 8 Hz), 7.85 (1H, d, J = 11 Hz), 4.98 (1H, q, J = 6 Hz), 2.54 (1H, brs), 2.14-1.96 (2H, m), 1.62 (9H, s), 1.08 (3H, t, J = 7 Hz);
MS (FAB) m/z: 323 [M+H]+.
1H-NMR (400MHz, CDCl3) δppm:
8.00-7.94 (3H, m), 7.90-7.87 (1H, m), 7.84-7.81 (1H, m), 7.06-7.04 (2H, m), 5.52 (1H, dd, J = 7, 6 Hz), 2.63-2.57 (1H, m), 2.34-2.25 (2H, m), 1.61 (9H, s), 1.21-1.18 (2H, m), 1.14 (3H, t, J = 7 Hz), 1.01-0.98 (2H, m);
MS (FAB+) m/z: 466 [M+H]+.
1H-NMR (400MHz, CDCl3) δppm:
8.14 (1H, t, J = 8 Hz), 8.01-7.89 (4H, m), 7.04 (2H, dd, J = 7, 2 Hz), 5.54 (1H, dd, J = 7, 6 Hz), 2.63-2.57 (1H, m), 2.35-2.21 (2H, m), 1.22-1.18 (2H, m), 1.15 (3H, q, J = 5 Hz), 1.02-0.99 (2H, m);
MS (FAB) m/z: 411 [M+H]+.
1H-NMR (400MHz, CDCl3) δppm:
7.97 (1H, t, J = 8 Hz), 7.90 (1H, d, J = 8 Hz), 7.84 (1H, d, J = 5 Hz), 5.18 (1H, q, J = 7 Hz), 1.73 (4H, d, J = 7 Hz), 1.60 (9H, s);
MS (FAB) m/z: 309 [M+H]+.
1H-NMR (400MHz, CDCl3) δppm:
8.02-7.94 (3H, m), 7.89 (1H, d, J = 8 Hz), 7.83 (1H, d, J = 8 Hz), 7.05 (2H, d, J = 8 Hz), 5.75 (1H, q, J = 7 Hz), 2.63-2.59 (1H, m), 1.92 (3H, d, J = 4 Hz), 1.48 (9H, s), 1.20 (2H, m), 1.01-0.99 (2H, m).
1H-NMR (400MHz, CDCl3) δppm:
8.14 (1H, t, J = 8 Hz), 8.01 (2H, d, J = 9 Hz), 7.98-7.96 (1H, m), 7.93-7.90 (1H, m), 7.06 (2H, d, J= 9 Hz), 5.76 (1H, q, J = 7 Hz), 2.64-2.57 (1H, m), 1.92 (3H, d, J= 7 Hz), 1.23-1.18 (2H, m), 1.03-0.98 (2H, m);
MS (FAB) m/z: 397 [M+H]+.
1H-NMR (400MHz, CDCl3) δppm:
8.20 (1H, t, J = 8 Hz), 8.04-7.95 (3H, m), 7.87 (1H, d, J = 12 Hz), 7.04 (2H, d, J = 9 Hz), 6.97-6.87 (1H, m), 5.53 (1H, t, J= 6 Hz), 4.44-4.37 (2H, m), 4.22 (1H, dd, J = 8, 6 Hz), 4.15 (1H, dd, J = 9, 6 Hz), 3.84-3.72 (2H, m), 3.19-3.16 (1H, m), 2.63-2.55 (1H, m), 2.35-2.18 (2H, m), 1.23-1.10 (5H, m), 1.03-0.96 (2H, m);
MS (FAB) m/z: 496 [M+H]+.
1H-NMR (400MHz, CDCl3) δppm:
8.19 (1H, t, J = 8 Hz), 8.02-7.97 (3H, m), 7.87 (1H, dd, J = 12, 1 Hz), 7.05 (2H, d, J = 9 Hz), 6.95-6.87 (1H, m), 5.76 (1H, q, J= 7 Hz), 4.44-4.37 (2H, m), 4.21 (1H, dd, J = 10, 5 Hz), 4.15 (1H, dd, J = 10, 5 Hz), 3.82 (1H, dd, J = 10, 3 Hz), 3.75 (1H, dd, J = 10, 3 Hz), 3.32 (1H, d, J = 2 Hz), 2.63-2.57 (1H, m), 1.92 (3H, d, J = 7 Hz), 1.22-1.19 (2H, m), 1.03-0.98 (2H, m);
MS (FAB) m/z: 482 [M+H]+.
1H-NMR (400MHz, CDCl3) δppm:
8.20 (1H, t, J = 8 Hz), 8.04-7.97 (3H, m), 7.87 (1H, dd, J = 12, 1 Hz), 7.06 (2H, d, J = 9 Hz), 6.97-6.87 (1H, m), 5.76 (1H, q, J= 7 Hz), 4.46-4.38 (2H, m), 4.22 (1H, dd, J = 10, 5 Hz), 4.15 (1H, dd, J = 10, 5 Hz), 3.82 (1H, dd, J = 10, 3 Hz), 3.75 (1H, dd, J = 10, 4 Hz), 3.21-3.18 (1H, m), 2.65-2.56 (1H, m), 1.92 (3H, d, J = 7 Hz), 1.24-1.18 (2H, m), 1.04-0.98 (2H, m);
MS (FAB) m/z: 482 [M+H]+.
1H-NMR (400MHz, CDCl3) δppm:
8.21 (1H, t, J = 8 Hz), 8.03-7.96 (3H, m), 7.89 (1H, dd, J = 13, 1 Hz), 7.42-7.24 (1H, m), 7.04 (2H, d, J= 9 Hz), 5.53 (1H, t, J = 7 Hz), 4.74-4.71 (1H, m), 4.56 (1H, t, J= 9 Hz), 4.41-4.34 (1H, m), 3.01-2.94 (1H, m), 2.63-2.57 (1H, m), 2.40-2.20 (3H, m), 1.22-1.18 (2H, m), 1.15 (3H, t, J= 7 Hz), 1.02-0.97 (2H, m);
MS (FAB) m/z: 494 [M+H]+.
1H-NMR (400MHz, CDCl3) δppm:
8.22 (1H, t, J = 8 Hz), 8.03-7.96 (3H, m), 7.89 (1H, dd, J = 13, 1 Hz), 7.42-7.37 (1H, m), 7.04 (2H, d, J= 9 Hz), 5.53 (1H, t, J = 7 Hz), 4.74-4.71 (1H, m), 4.56 (1H, t, J= 9 Hz), 4.41-4.34 (1H, m), 3.01-2.94 (1H, m), 2.63-2.57 (1H, m), 2.40-2.20 (3H, m), 1.22-1.18 (2H, m), 1.15 (3H, t, J= 7 Hz), 1.02-0.97 (2H, m);
MS (FAB) m/z: 494 [M+H]+.
1H-NMR (400MHz, CDCl3) δppm:
8.20 (1H, t, J = 8 Hz), 8.03-7.97 (3H, m), 7.89 (1H, dd, J = 13, 2 Hz), 7.05-6.96 (3H, m), 5.53 (1H, t, J= 7 Hz), 4.98-4.88 (1H, m), 4.66 (1H, dd, J = 10, 6 Hz), 4.37 (1H, dd, J = 10, 4 Hz), 3.01 (1H, dd, J = 18, 8 Hz), 2.67-2.55 (2H, m), 2.35-2.19 (2H, m), 1.23-1.10 (5H, m), 1.02-0.97 (2H, m);
MS (FAB) m/z: 494 [M+H]+.
1H-NMR (400MHz, CDCl3) δppm:
8.21 (1H, t, J = 8 Hz), 8.03-7.96 (3H, m), 7.87 (1H, dd, J = 12, 1 Hz), 7.34-7.27 (1H, m), 7.04 (2H, d, J= 9 Hz), 5.98-5.90 (1H, m), 5.53 (1H, t, J= 6 Hz), 4.62-4.55 (1H, m), 3.50-3.45 (2H, m), 2.97-2.89 (1H, m), 2.63-2.57 (1H, m), 2.35-2.19 (2H, m), 2.18-2.05 (1H, m), 1.23-1.17 (2H, m), 1.14 (3H, t, J = 7 Hz), 1.04-0.97 (2H, m);
MS (ESI) m/z: 493 [M+H]+.
1H-NMR (400MHz, CDCl3) δppm:
8.21 (1H, t, J = 8 Hz), 8.03-7.97 (3H, m), 7.88 (1H, dd, J = 12, 1 Hz), 7.34-7.27 (1H, m), 7.03 (2H, d, J= 9 Hz), 5.81-5.75 (1H, m), 5.53 (1H, t, J= 6 Hz), 4.63-4.55 (1H, m), 3.51-3.42 (2H, m), 2.96-2.88 (1H, m), 2.64-2.56 (1H, m), 2.35-2.19 (2H, m), 2.18-2.05 (1H, m), 1.23-1.17 (2H, m), 1.14 (3H, t, J = 7 Hz), 1.03-0.97 (2H, m);
MS (ESI) m/z: 493 [M+H]+.
1H-NMR (500MHz, CDCl3) δppm:
8.21 (1H, t, J = 8 Hz), 8.06-7.97 (3H, m), 7.92 (1H, dd, J = 13, 1 Hz), 7.64-7.57 (1H, m), 7.04 (2H, d, J = 9 Hz), 5.54 (1H, dd, J = 7, 6 Hz), 5.40-5.38 (1H, m), 4.69-4.60 (2H, m), 4.57-4.51 (1H, m), 4.21-4.14 (1H, m), 2.63-2.57 (1H, m), 2.36-2.20 (2H, m), 1.22-1.18 (2H, m), 1.15 (3H, t, J = 7 Hz), 1.03-0.97 (2H, m);
MS (ES) m/z: 510 [M+H]+.
1H-NMR (400MHz, CDCl3) δppm:
8.21 (1H, t, J = 8 Hz), 8.02-7.97 (3H, m), 7.87 (1H, dd, J = 12, 1 Hz), 7.34-7.30 (1H, m), 7.05 (2H, d, J= 9 Hz), 5.78-5.74 (2H, m), 4.62-4.54 (1H, m), 3.49-3.45 (2H, m), 2.98-2.89 (1H, m), 2.64-2.57 (1H, m), 2.17-2.07 (1H, m), 1.92 (3H, d, J = 7 Hz), 1.22-1.18 (2H, m), 1.03-0.97 (2H, m);
MS (ESI) m/z: 479 [M+H]+.
1H-NMR (400MHz, CDCl3) δppm:
8.21 (1H, t, J = 8 Hz), 8.08-7.96 (3H, m), 7.87 (1H, dd, J = 12, 1 Hz), 7.38-7.30 (1H, m), 7.06 (2H, d, J= 9 Hz), 5.90-5.75 (2H, m), 4.64-4.55 (1H, m), 3.53-3.43 (2H, m), 2.98-2.89 (1H, m), 2.68-2.57 (1H, m), 2.19-2.07 (1H, m), 1.92 (3H, d, J = 7 Hz), 1.25-1.17 (2H, m), 1.09-0.96 (2H, m);
MS(ESI) m/z: 479 [M+H]+.
1H-NMR (500MHz, CDCl3) δppm:
8.20 (1H, t, J = 8 Hz), 8.02-7.97 (3H, m), 7.89 (1H, d, J = 12 Hz), 7.35-7.28 (1H, m), 7.04 (2H, d, J = 9 Hz), 5.53 (1H, dd J = 7, 6 Hz), 4.09-4.86 (2H, m), 4.54 (1H, dd, J= 11, 1 Hz), 4.49 (1H, d, J = 11 Hz), 2.64-2.56 (2H, m), 2.36-2.20 (2H, m), 1.22-1.17 (2H, m), 1.15 (3H, t, J = 7 Hz), 1.02-0.98 (2H, m);
MS (ES) m/z: 510 [M+H]+.
1H-NMR (400MHz, CDCl3) δppm:
8.20 (1H, t, J = 8 Hz), 8.02-7.96 (3H, m), 7.86 (1H, dd, J = 12, 1 Hz), 7.47-7.42 (1H, m), 7.05 (2H, d, J= 9 Hz), 5.76 (1H, q, J = 7 Hz), 4.70-4.63 (1H, m), 4.54-4.49 (1H, m), 4.22 (1H, dd, J = 9, 8 Hz), 4.07 (1H, dd, J = 10, 4 Hz), 3.87 (1H, dd, J = 10, 2 Hz), 3.72 (1H, dd, J = 9, 7 Hz), 2.63-2.57 (1H, m), 2.29-2.23 (1H, m), 1.92 (3H, d, J= 7 Hz), 1.22-1.18 (2H, m), 1.03-0.98 (2H, m);
MS (FAB) m/z: 482 [M+H]+.
1H-NMR (400MHz, CDCl3) δppm:
8.21 (1H, t, J = 8 Hz), 8.02-7.96 (3H, m), 7.87 (1H, dd, J = 12, 1 Hz), 7.47-7.42 (1H, m), 7.05 (2H, d, J= 9 Hz), 5.76 (1H, q, J = 7 Hz), 4.70-4.63 (1H, m), 4.54-4.49 (1H, m), 4.23 (1H, dd, J = 9, 8 Hz), 4.07 (1H, dd, J = 10, 4 Hz), 3.88 (1H, dd, J = 10, 2 Hz), 3.72 (1H, dd, J = 9, 7 Hz), 2.63-2.57 (1H, m), 2.15 (1H, d, J = 5 Hz), 1.92 (3H, d, J = 7 Hz), 1.22-1.18 (2H, m), 1.03-0.98 (2H, m);
MS (FAB) m/z: 482 [M+H]+.
実施例で得られた化合物5g、乳糖90g、トウモロコシデンプン34g、結晶セルロース20gおよびステアリン酸マグネシウム1gをブレンダーで混合した後、打錠機で打錠することにより、錠剤が得られる。
化合物の投与液は、0.5w/v%メチルセルロース溶液を用い、メノウ乳鉢で粉砕しながら1mg/mLの濃度になるように懸濁液を調製した。動物は、雄性C57/BL6Jマウス(日本チャールスリバー株式会社)を6週齢から8週齢で入荷し、9週齢から13週齢で使用した。試験日前日の17時から18時の間を目安に絶食を開始し、16時間から17時間程度の絶食下で試験を開始した。各群5匹ずつを用いた。尾静脈から採血を行った後、化合物懸濁液を10mg/kgとなるように経口投与した。陰性対照群には0.5w/v%メチルセルロース溶液を投与した。経口投与から25分後に尾静脈から採血を行い、経口投与から30分後に30w/v%グルコース溶液を10mL/kgで経口投与した。グルコース負荷から15分、30分、60分、120分後に尾静脈から採血を行った。採取した血液を遠心して血漿を分取し、Glucoroder-GXT(株式会社エイアンドティー)で血漿血糖値(mg/dL)を測定した。個体毎に、糖負荷5分前、糖負荷15分、30 分、60分、120分後の血糖値を用いてAUC(mg/dL・min)を算出した。群毎におけるAUC平均値を算出し、陰性対照群と比較したAUC低下率(%)を算出し、薬効の指標とした。
化合物を秤量し、溶媒(0.5w/v%メチルセルロースまたは20w/v%シクロデキストリン)中で1~10mg/mLの濃度になるように懸濁し、投与液を調製する。化合物の用量をふる場合は調製した投与液を前記溶媒を用いて順次希釈し、投与液を調製する。動物はZucker fatty ラット(日本チャールスリバー)またはZucker daiabetic fatty(ZDF) ラット(日本チャールスリバー)、雄10~18週齢を使用する。試験の2日前に血糖値、体重、血中インスリン値を測定し、各パラメータが均等になるように各群n=5から8に割り付ける。試験実施日の前日15時頃に絶食を行う。試験当日、ラットに前述の方法によって調製される化合物投与液を1~5mL/kgで経口投与し、その30分後に25~50w/v%グルコース溶液を4mL/kgで経口投与する。採血は化合物投与前、グルコース投与5分前、グルコース投与30、60、120および180分後に、ラット尾静脈より行う。得られた血液を遠心後プラズマを分離し、プラズマ血糖値をGlucoroder-GXT(株式会社エイアンドティー)で測定する。各群におけるグルコース投与後の血糖値のAUCを算出し、vehicle投与群の血糖値AUCに対する低下率(%)を化合物の薬効として表記する。
Junko Ogawa, et al., Life Sciences Vol.65, No.12 pp.1287-1296 (1999) に記載の方法を参照して被検化合物のβ細胞(膵臓)保護作用を確認することができる。
Claims (8)
- 以下:
4-(5-{(1R)-1-[4-(シクロプロピルカルボニル)フェノキシ]プロピル}-1,2,4-オキサジアゾール-3-イル)-2-フルオロ-N-[(3S,4R)-4-ヒドロキシテトラヒドロフラン-3-イル]ベンズアミド;
4-(5-{(1R)-1-[4-(シクロプロピルカルボニル)フェノキシ]プロピル}-1,2,4-オキサジアゾール-3-イル)-2-フルオロ-N-[(3R,4S)-4-ヒドロキシテトラヒドロフラン-3-イル]ベンズアミド;
4-(5-{(1R)-1-[4-(シクロプロピルカルボニル)フェノキシ]エチル}-1,2,4-オキサジアゾール-3-イル)-2-フルオロ-N-[(3R,4S)-4-ヒドロキシテトラヒドロフラン-3-イル]ベンズアミド;
4-(5-{(1R)-1-[4-(シクロプロピルカルボニル)フェノキシ]エチル}-1,2,4-オキサジアゾール-3-イル)-2-フルオロ-N-[(3S,4R)-4-ヒドロキシテトラヒドロフラン-3-イル]ベンズアミド;
4-(5-{(1R)-1-[4-(シクロプロピルカルボニル)フェノキシ]プロピル}-1,2,4-オキサジアゾール-3-イル)-2-フルオロ-N-[(3R)-2-オキソテトラヒドロフラン-3-イル]ベンズアミド;
4-(5-{(1R)-1-[4-(シクロプロピルカルボニル)フェノキシ]プロピル}-1,2,4-オキサジアゾール-3-イル)-2-フルオロ-N-[(3S)-2-オキソテトラヒドロフラン-3-イル]ベンズアミド;
4-(5-{(1R)-1-[4-(シクロプロピルカルボニル)フェノキシ]プロピル}-1,2,4-オキサジアゾール-3-イル)-2-フルオロ-N-[(3S)-5-オキソテトラヒドロフラン-3-イル]ベンズアミド;
4-(5-{(1R)-1-[4-(シクロプロピルカルボニル)フェノキシ]プロピル}-1,2,4-オキサジアゾール-3-イル)-2-フルオロ-N-[(3R)-2-オキソピロリジン-3-イル]ベンズアミド;
4-(5-{(1R)-1-[4-(シクロプロピルカルボニル)フェノキシ]プロピル}-1,2,4-オキサジアゾール-3-イル)-2-フルオロ-N-[(3S)-2-オキソピロリジン-3-イル]ベンズアミド;
4-(5-{(1R)-1-[4-(シクロプロピルカルボニル)フェノキシ]プロピル}-1,2,4-オキサジアゾール-3-イル)-2-フルオロ-N-[(3S,4S)-4-ヒドロキシ-2-オキソテトラヒドロフラン-3-イル]ベンズアミド;
4-(5-{(1R)-1-[4-(シクロプロピルカルボニル)フェノキシ]エチル}-1,2,4-オキサジアゾール-3-イル)-2-フルオロ-N-[(3R)-2-オキソピロリジン-3-イル]ベンズアミド;
4-(5-{(1R)-1-[4-(シクロプロピルカルボニル)フェノキシ]エチル}-1,2,4-オキサジアゾール-3-イル)-2-フルオロ-N-[(3S)-2-オキソピロリジン-3-イル]ベンズアミド;
4-(5-{(1R)-1-[4-(シクロプロピルカルボニル)フェノキシ]プロピル}-1,2,4-オキサジアゾール-3-イル)-2-フルオロ-N-[(3S,4R)-4-ヒドロキシ-2-オキソテトラヒドロフラン-3-イル]ベンズアミド;
4-(5-{(1R)-1-[4-(シクロプロピルカルボニル)フェノキシ]エチル}-1,2,4-オキサジアゾール-3-イル)-2-フルオロ-N-[(3R,4R)-4-ヒドロキシテトラヒドロフラン-3-イル]ベンズアミド;および
4-(5-{(1R)-1-[4-(シクロプロピルカルボニル)フェノキシ]エチル}-1,2,4-オキサジアゾール-3-イル)-2-フルオロ-N-[(3S,4S)-4-ヒドロキシテトラヒドロフラン-3-イル]ベンズアミド;
からなる群より選択される化合物またはその薬学的に許容され得る塩。 - 請求項1または2に記載の化合物またはその薬学的に許容され得る塩を有効成分として含有する医薬組成物。
- 1型糖尿病、2型糖尿病または肥満を治療するための、請求項3に記載の医薬組成物。
- β細胞または膵臓を保護するための、請求項3に記載の医薬組成物。
- 医薬組成物を製造するための、請求項1または2に記載の化合物またはその薬学的に許容され得る塩の使用。
- 請求項1または2に記載の化合物またはその薬学的に許容され得る塩を哺乳動物に投与することを含む、疾病を治療する方法。
- 哺乳動物がヒトである請求項7に記載の方法。
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RU2014102743/04A RU2014102743A (ru) | 2011-07-29 | 2012-07-27 | Амидное производное, замещенное n-гетероциклическим кольцом |
JP2013526870A JP5973440B2 (ja) | 2011-07-29 | 2012-07-27 | N−ヘテロ環置換アミド誘導体 |
BR112014001767A BR112014001767A2 (pt) | 2011-07-29 | 2012-07-27 | composto, composição farmaccêutica, uso de um composto, e, método para o tratamento de uma doença |
EP12820526.7A EP2738168B1 (en) | 2011-07-29 | 2012-07-27 | N-hetero-ring-substituted amide derivative |
CA2843238A CA2843238C (en) | 2011-07-29 | 2012-07-27 | N-hetero-ring-substituted amide derivative |
NZ620339A NZ620339B2 (en) | 2011-07-29 | 2012-07-27 | N-hetero-ring-substituted amide derivative |
US14/235,331 US9006273B2 (en) | 2011-07-29 | 2012-07-27 | N-hetero-ring-substituted amide derivative |
CN201280047243.XA CN103827111B (zh) | 2011-07-29 | 2012-07-27 | N-杂环取代酰胺衍生物 |
MX2014000929A MX2014000929A (es) | 2011-07-29 | 2012-07-27 | Derivados de amida sustituidos con n-hetero-anillo. |
AU2012291150A AU2012291150A1 (en) | 2011-07-29 | 2012-07-27 | N-hetero-ring-substituted amide derivative |
KR1020147001993A KR20140051912A (ko) | 2011-07-29 | 2012-07-27 | N-헤테로 고리 치환 아미드 유도체 |
ZA2014/00407A ZA201400407B (en) | 2011-07-29 | 2014-01-17 | N-hetero-ring-substituted amide derivative |
IL230655A IL230655A0 (en) | 2011-07-29 | 2014-01-26 | Derivatives n-hetero-converted in the amide ring, preparations containing them and their uses |
HK14111721.7A HK1198033A1 (zh) | 2011-07-29 | 2014-11-20 | -雜環取代醯胺衍生物 |
Applications Claiming Priority (2)
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JP2011166248 | 2011-07-29 | ||
JP2011-166248 | 2011-07-29 |
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WO2013018675A1 true WO2013018675A1 (ja) | 2013-02-07 |
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PCT/JP2012/069098 WO2013018675A1 (ja) | 2011-07-29 | 2012-07-27 | N-ヘテロ環置換アミド誘導体 |
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US (1) | US9006273B2 (ja) |
EP (1) | EP2738168B1 (ja) |
JP (1) | JP5973440B2 (ja) |
KR (1) | KR20140051912A (ja) |
CN (1) | CN103827111B (ja) |
AU (1) | AU2012291150A1 (ja) |
BR (1) | BR112014001767A2 (ja) |
CA (1) | CA2843238C (ja) |
CO (1) | CO6862161A2 (ja) |
HK (1) | HK1198033A1 (ja) |
IL (1) | IL230655A0 (ja) |
MX (1) | MX2014000929A (ja) |
RU (1) | RU2014102743A (ja) |
TW (1) | TWI529169B (ja) |
WO (1) | WO2013018675A1 (ja) |
ZA (1) | ZA201400407B (ja) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013108800A1 (ja) * | 2012-01-18 | 2013-07-25 | 第一三共株式会社 | 置換フェニルアゾール誘導体 |
WO2015170775A1 (ja) * | 2014-05-09 | 2015-11-12 | 日産化学工業株式会社 | 置換アゾール化合物及び糖尿病治療薬 |
CN105181861A (zh) * | 2015-04-24 | 2015-12-23 | 上海应用技术学院 | 一种利用柱前衍生对3-氨基吡咯烷盐酸盐进行分析的方法 |
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- 2012-07-27 KR KR1020147001993A patent/KR20140051912A/ko not_active Application Discontinuation
- 2012-07-27 MX MX2014000929A patent/MX2014000929A/es unknown
- 2012-07-27 EP EP12820526.7A patent/EP2738168B1/en not_active Not-in-force
- 2012-07-27 CA CA2843238A patent/CA2843238C/en not_active Expired - Fee Related
- 2012-07-27 RU RU2014102743/04A patent/RU2014102743A/ru not_active Application Discontinuation
- 2012-07-27 AU AU2012291150A patent/AU2012291150A1/en not_active Abandoned
- 2012-07-27 JP JP2013526870A patent/JP5973440B2/ja not_active Expired - Fee Related
- 2012-07-27 BR BR112014001767A patent/BR112014001767A2/pt not_active IP Right Cessation
- 2012-07-27 US US14/235,331 patent/US9006273B2/en not_active Expired - Fee Related
- 2012-07-27 WO PCT/JP2012/069098 patent/WO2013018675A1/ja active Application Filing
- 2012-07-27 TW TW101127098A patent/TWI529169B/zh active
- 2012-07-27 CN CN201280047243.XA patent/CN103827111B/zh not_active Expired - Fee Related
-
2014
- 2014-01-17 ZA ZA2014/00407A patent/ZA201400407B/en unknown
- 2014-01-26 IL IL230655A patent/IL230655A0/en unknown
- 2014-01-28 CO CO14016982A patent/CO6862161A2/es active IP Right Grant
- 2014-11-20 HK HK14111721.7A patent/HK1198033A1/zh not_active IP Right Cessation
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2013108800A1 (ja) * | 2012-01-18 | 2013-07-25 | 第一三共株式会社 | 置換フェニルアゾール誘導体 |
US9233958B2 (en) | 2012-01-18 | 2016-01-12 | Daiichi Sankyo Company, Limited | Substituted phenylazole derivatives |
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WO2015170775A1 (ja) * | 2014-05-09 | 2015-11-12 | 日産化学工業株式会社 | 置換アゾール化合物及び糖尿病治療薬 |
CN105181861A (zh) * | 2015-04-24 | 2015-12-23 | 上海应用技术学院 | 一种利用柱前衍生对3-氨基吡咯烷盐酸盐进行分析的方法 |
Also Published As
Publication number | Publication date |
---|---|
BR112014001767A2 (pt) | 2017-02-14 |
CA2843238A1 (en) | 2013-02-07 |
TW201309687A (zh) | 2013-03-01 |
AU2012291150A1 (en) | 2014-02-20 |
EP2738168B1 (en) | 2016-04-06 |
KR20140051912A (ko) | 2014-05-02 |
JP5973440B2 (ja) | 2016-08-23 |
ZA201400407B (en) | 2014-11-26 |
TWI529169B (zh) | 2016-04-11 |
HK1198033A1 (zh) | 2015-03-06 |
NZ620339A (en) | 2016-02-26 |
IL230655A0 (en) | 2014-03-31 |
CN103827111A (zh) | 2014-05-28 |
CA2843238C (en) | 2016-08-30 |
CO6862161A2 (es) | 2014-02-10 |
JPWO2013018675A1 (ja) | 2015-03-05 |
MX2014000929A (es) | 2014-05-12 |
US9006273B2 (en) | 2015-04-14 |
EP2738168A1 (en) | 2014-06-04 |
RU2014102743A (ru) | 2015-09-10 |
CN103827111B (zh) | 2016-03-23 |
US20140221437A1 (en) | 2014-08-07 |
EP2738168A4 (en) | 2015-03-04 |
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