TWI588136B - 多環類衍生物、其製備方法及其在醫藥上的應用 - Google Patents
多環類衍生物、其製備方法及其在醫藥上的應用 Download PDFInfo
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- TWI588136B TWI588136B TW102100678A TW102100678A TWI588136B TW I588136 B TWI588136 B TW I588136B TW 102100678 A TW102100678 A TW 102100678A TW 102100678 A TW102100678 A TW 102100678A TW I588136 B TWI588136 B TW I588136B
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- compound
- cycloalkyl
- mmol
- alkyl
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- 238000002360 preparation method Methods 0.000 title claims description 12
- 125000003367 polycyclic group Chemical group 0.000 title description 14
- 150000001875 compounds Chemical class 0.000 claims description 111
- 239000000203 mixture Substances 0.000 claims description 86
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 84
- 125000000623 heterocyclic group Chemical group 0.000 claims description 79
- 125000000217 alkyl group Chemical group 0.000 claims description 75
- 125000001072 heteroaryl group Chemical group 0.000 claims description 66
- 125000003118 aryl group Chemical group 0.000 claims description 58
- 150000003839 salts Chemical class 0.000 claims description 51
- 125000003545 alkoxy group Chemical group 0.000 claims description 35
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- 229910052736 halogen Inorganic materials 0.000 claims description 32
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- 238000000034 method Methods 0.000 claims description 32
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- 101000912510 Homo sapiens Free fatty acid receptor 1 Proteins 0.000 claims description 27
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- 239000008194 pharmaceutical composition Substances 0.000 claims description 20
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 18
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- 206010012601 diabetes mellitus Diseases 0.000 claims description 15
- 125000001424 substituent group Chemical group 0.000 claims description 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 13
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 12
- 125000005842 heteroatom Chemical group 0.000 claims description 7
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- 238000006482 condensation reaction Methods 0.000 claims description 5
- DGENZVKCTGIDRZ-UHFFFAOYSA-N 3-[4-[(3-phenoxyphenyl)methylamino]phenyl]propanoic acid Chemical compound C1=CC(CCC(=O)O)=CC=C1NCC1=CC=CC(OC=2C=CC=CC=2)=C1 DGENZVKCTGIDRZ-UHFFFAOYSA-N 0.000 claims description 4
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- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 3
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- 238000006467 substitution reaction Methods 0.000 claims description 3
- 125000004185 ester group Chemical group 0.000 claims description 2
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- 150000001735 carboxylic acids Chemical group 0.000 claims 3
- 125000001475 halogen functional group Chemical group 0.000 claims 2
- XLJMAIOERFSOGZ-UHFFFAOYSA-N cyanic acid Chemical compound OC#N XLJMAIOERFSOGZ-UHFFFAOYSA-N 0.000 claims 1
- 125000004404 heteroalkyl group Chemical group 0.000 claims 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 186
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- 238000004949 mass spectrometry Methods 0.000 description 63
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 60
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- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 28
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 27
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- 125000006268 biphenyl-3-yl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C1=C([H])C(*)=C([H])C([H])=C1[H] 0.000 description 26
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 26
- 238000005481 NMR spectroscopy Methods 0.000 description 24
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 20
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 19
- 239000003480 eluent Substances 0.000 description 19
- 229910000024 caesium carbonate Inorganic materials 0.000 description 18
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- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 16
- 239000008103 glucose Substances 0.000 description 16
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 16
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- 238000012360 testing method Methods 0.000 description 15
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- ZTDWGMYBAYEBDZ-ISKFKSNPSA-N 2-[(3s)-6-[[3-[2,6-dimethyl-4-[(3r)-oxolan-3-yl]oxyphenyl]phenyl]methoxy]-2,3-dihydro-1-benzofuran-3-yl]acetic acid Chemical compound C=1C(C)=C(C=2C=C(COC=3C=C4OC[C@@H](CC(O)=O)C4=CC=3)C=CC=2)C(C)=CC=1O[C@@H]1CCOC1 ZTDWGMYBAYEBDZ-ISKFKSNPSA-N 0.000 description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 13
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- 125000006413 ring segment Chemical group 0.000 description 13
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- OBEDIUDGEVLUGG-HSZRJFAPSA-N 2-[(3s)-6-[[3-(2,6-dimethyl-4-piperidin-4-yloxyphenyl)phenyl]methoxy]-2,3-dihydro-1-benzofuran-3-yl]acetic acid Chemical compound C=1C(C)=C(C=2C=C(COC=3C=C4OC[C@@H](CC(O)=O)C4=CC=3)C=CC=2)C(C)=CC=1OC1CCNCC1 OBEDIUDGEVLUGG-HSZRJFAPSA-N 0.000 description 8
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
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- KHXQGLSTCGSGLW-RXMQYKEDSA-N [(3r)-oxolan-3-yl] methanesulfonate Chemical compound CS(=O)(=O)O[C@@H]1CCOC1 KHXQGLSTCGSGLW-RXMQYKEDSA-N 0.000 description 7
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- VMSCNYLKNKMHAP-HXUWFJFHSA-N methyl 2-[(3s)-6-[[3-(4-hydroxy-2,6-dimethylphenyl)phenyl]methoxy]-2,3-dihydro-1-benzofuran-3-yl]acetate Chemical compound C([C@H](C1=CC=2)CC(=O)OC)OC1=CC=2OCC(C=1)=CC=CC=1C1=C(C)C=C(O)C=C1C VMSCNYLKNKMHAP-HXUWFJFHSA-N 0.000 description 7
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- 125000003342 alkenyl group Chemical group 0.000 description 6
- 125000003282 alkyl amino group Chemical group 0.000 description 6
- 125000000304 alkynyl group Chemical group 0.000 description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 6
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- ZTDWGMYBAYEBDZ-VWNXMTODSA-N 2-[(3s)-6-[[3-[2,6-dimethyl-4-[(3s)-oxolan-3-yl]oxyphenyl]phenyl]methoxy]-2,3-dihydro-1-benzofuran-3-yl]acetic acid Chemical compound C=1C(C)=C(C=2C=C(COC=3C=C4OC[C@@H](CC(O)=O)C4=CC=3)C=CC=2)C(C)=CC=1O[C@H]1CCOC1 ZTDWGMYBAYEBDZ-VWNXMTODSA-N 0.000 description 5
- NDRQMEQFSNUGMV-OAQYLSRUSA-N 2-[(3s)-6-[[3-[4-(azetidin-3-yloxy)-2,6-dimethylphenyl]phenyl]methoxy]-2,3-dihydro-1-benzofuran-3-yl]acetic acid Chemical compound C=1C(C)=C(C=2C=C(COC=3C=C4OC[C@@H](CC(O)=O)C4=CC=3)C=CC=2)C(C)=CC=1OC1CNC1 NDRQMEQFSNUGMV-OAQYLSRUSA-N 0.000 description 5
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D307/80—Radicals substituted by oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Diabetes (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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| WO2015062486A1 (en) * | 2013-10-31 | 2015-05-07 | Sunshine Lake Pharma Co., Ltd. | Biphenyl compounds and uses thereof |
| CN104650055A (zh) * | 2013-11-22 | 2015-05-27 | 山东轩竹医药科技有限公司 | 芳香多环羧酸衍生物 |
| CN104788412B (zh) * | 2014-01-22 | 2017-02-15 | 山东轩竹医药科技有限公司 | 芳香多环羧酸衍生物 |
| WO2016022448A1 (en) | 2014-08-08 | 2016-02-11 | Merck Sharp & Dohme Corp. | Antidiabetic bicyclic compounds |
| WO2016022742A1 (en) | 2014-08-08 | 2016-02-11 | Merck Sharp & Dohme Corp. | Antidiabetic bicyclic compounds |
| WO2016019587A1 (en) | 2014-08-08 | 2016-02-11 | Merck Sharp & Dohme Corp. | [7, 6]-fused bicyclic antidiabetic compounds |
| US10100042B2 (en) | 2014-08-08 | 2018-10-16 | Merck Sharp & Dohme Corp. | [5,6]—fused bicyclic antidiabetic compounds |
| EP3206756B1 (de) | 2014-10-14 | 2018-09-19 | Basf Se | Verwendung von hexadeca-8,15-dienal als aromachemikalie |
| CN106478616B (zh) * | 2015-08-27 | 2020-05-12 | 江苏恒瑞医药股份有限公司 | 一种gpr40激动剂的结晶形式及其制备方法 |
| CN108236609B (zh) * | 2016-12-27 | 2022-10-21 | 江苏恒瑞医药股份有限公司 | 一种gpr40激动剂药物组合物及其制备方法 |
| CN108236611A (zh) * | 2016-12-27 | 2018-07-03 | 江苏恒瑞医药股份有限公司 | 两种化合物联合在制备治疗糖尿病药物中的用途 |
| SI3752501T1 (sl) | 2018-02-13 | 2023-08-31 | Gilead Sciences, Inc. | Inhibitorji pd-1/pd-l1 |
| CA3093130C (en) | 2018-04-19 | 2023-10-17 | Gilead Sciences, Inc. | Pd-1/pd-l1 inhibitors |
| SI3820572T1 (sl) | 2018-07-13 | 2023-12-29 | Gilead Sciences, Inc. | Inhibitorji pd-1/pd-l1 |
| JP7158577B2 (ja) | 2018-10-24 | 2022-10-21 | ギリアード サイエンシーズ， インコーポレイテッド | Ｐｄ－１／ｐｄ－ｌ１阻害剤 |
| JP2022552655A (ja) | 2019-10-07 | 2022-12-19 | キャリーオペ，インク． | Ｇｐｒ１１９アゴニスト |
| TW202140440A (zh) | 2020-02-28 | 2021-11-01 | 美商克力歐普股份有限公司 | Gpr40激動劑 |
| AU2021275038A1 (en) | 2020-05-19 | 2022-12-22 | Kallyope, Inc. | AMPK activators |
| CA3183575A1 (en) | 2020-06-26 | 2021-12-30 | Iyassu Sebhat | Ampk activators |
| CN114163426B (zh) * | 2020-09-10 | 2024-03-19 | 上海爱博医药科技有限公司 | 苯并含氧杂环类化合物及其医药应用 |
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| US20060258722A1 (en) * | 2003-05-30 | 2006-11-16 | Takeda Pharmaceutical Company., Ltd. | Condensed ring compound |
| CN101616913A (zh) * | 2006-06-27 | 2009-12-30 | 武田药品工业株式会社 | 稠环化合物 |
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| MX9700557A (es) * | 1994-07-22 | 1997-12-31 | Byk Gulden Lomberg Chem Fab | Dihidrobenzofuranos. |
| WO2005019151A1 (en) | 2003-08-20 | 2005-03-03 | Eli Lilly And Company | Ppar modulators |
| US7834013B2 (en) | 2003-11-19 | 2010-11-16 | Glaxosmithkline Llc | Aminophenylcyclopropyl carboxylic acids and derivatives as agonists to GPR40 |
| CA2551610A1 (en) * | 2003-12-25 | 2005-07-14 | Takeda Pharmaceutical Company Limited | 3-(4-benzyloxyphenyl)propanoic acid derivatives |
| JP4074616B2 (ja) * | 2003-12-25 | 2008-04-09 | 武田薬品工業株式会社 | ３−（４−ベンジルオキシフェニル）プロパン酸誘導体 |
| JP4875978B2 (ja) | 2004-03-15 | 2012-02-15 | 武田薬品工業株式会社 | アミノフェニルプロパン酸誘導体 |
| JP2008500358A (ja) * | 2004-05-25 | 2008-01-10 | メタボレックス インコーポレーティッド | Ｐｐａｒのモジュレーターとしての、二環式の置換されたトリアゾール、およびこれらの調製方法 |
| JP2009530281A (ja) * | 2006-03-14 | 2009-08-27 | アムジエン・インコーポレーテツド | 代謝障害の治療に有用である二環式カルボン酸誘導体 |
| CA2740366A1 (en) * | 2008-10-21 | 2010-04-29 | Metabolex, Inc. | Aryl gpr120 receptor agonists and uses thereof |
| AR074760A1 (es) * | 2008-12-18 | 2011-02-09 | Metabolex Inc | Agonistas del receptor gpr120 y usos de los mismos en medicamentos para el tratamiento de diabetes y el sindrome metabolico. |
| RU2529860C2 (ru) | 2009-01-30 | 2014-10-10 | Тояма Кемикал Ко., Лтд. | Производное n-ацилантраниловой кислоты или его соль |
| CN102421739A (zh) * | 2009-04-22 | 2012-04-18 | 安斯泰来制药株式会社 | 羧酸化合物 |
| EP2440541A1 (en) | 2009-06-09 | 2012-04-18 | Takeda Pharmaceutical Company Limited | Novel fused cyclic compound and use thereof |
| CN102153553A (zh) | 2010-02-11 | 2011-08-17 | 山东轩竹医药科技有限公司 | 含有氨基磺酰胺基氮杂环丁烷的口服碳青霉烯化合物 |
| US8299117B2 (en) * | 2010-06-16 | 2012-10-30 | Metabolex Inc. | GPR120 receptor agonists and uses thereof |
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- 2012-12-27 CA CA2860353A patent/CA2860353A1/en not_active Abandoned
- 2012-12-27 UA UAA201408867A patent/UA115975C2/uk unknown
- 2012-12-27 WO PCT/CN2012/087606 patent/WO2013104257A1/zh not_active Ceased
- 2012-12-27 EP EP12865081.9A patent/EP2803664B1/en not_active Not-in-force
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- 2012-12-27 BR BR112014016648-0A patent/BR112014016648B1/pt not_active IP Right Cessation
- 2012-12-27 MX MX2014008125A patent/MX357780B/es active IP Right Grant
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060258722A1 (en) * | 2003-05-30 | 2006-11-16 | Takeda Pharmaceutical Company., Ltd. | Condensed ring compound |
| CN101616913A (zh) * | 2006-06-27 | 2009-12-30 | 武田药品工业株式会社 | 稠环化合物 |
Also Published As
| Publication number | Publication date |
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| WO2013104257A1 (zh) | 2013-07-18 |
| CN103429581B (zh) | 2015-08-26 |
| AU2012365706B2 (en) | 2015-08-20 |
| JP2015503595A (ja) | 2015-02-02 |
| BR112014016648B1 (pt) | 2020-10-27 |
| RU2621039C1 (ru) | 2017-05-31 |
| AU2012365706A1 (en) | 2014-07-24 |
| KR20140117498A (ko) | 2014-10-07 |
| BR112014016648A8 (pt) | 2017-07-04 |
| TW201329058A (zh) | 2013-07-16 |
| HK1188781A1 (zh) | 2014-05-16 |
| EP2803664A1 (en) | 2014-11-19 |
| JP6122871B2 (ja) | 2017-04-26 |
| UA115975C2 (uk) | 2018-01-25 |
| CA2860353A1 (en) | 2013-07-18 |
| BR112014016648A2 (pt) | 2017-06-13 |
| EP2803664B1 (en) | 2018-11-21 |
| CN103429581A (zh) | 2013-12-04 |
| MX357780B (es) | 2018-07-24 |
| KR102036547B1 (ko) | 2019-10-25 |
| ZA201404625B (en) | 2015-11-25 |
| US9139548B2 (en) | 2015-09-22 |
| EP2803664A4 (en) | 2015-10-28 |
| MX2014008125A (es) | 2014-09-22 |
| US20150005282A1 (en) | 2015-01-01 |
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