KR20120051777A - 스피로피페리딘 화합물 및 당뇨병의 치료를 위한 그의 제약 용도 - Google Patents
스피로피페리딘 화합물 및 당뇨병의 치료를 위한 그의 제약 용도 Download PDFInfo
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- KR20120051777A KR20120051777A KR1020127009501A KR20127009501A KR20120051777A KR 20120051777 A KR20120051777 A KR 20120051777A KR 1020127009501 A KR1020127009501 A KR 1020127009501A KR 20127009501 A KR20127009501 A KR 20127009501A KR 20120051777 A KR20120051777 A KR 20120051777A
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- South Korea
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- phenyl
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- 206010012601 diabetes mellitus Diseases 0.000 title claims abstract description 10
- JUXAVSAMVBLDKO-UHFFFAOYSA-N 1-(1-azabicyclo[2.2.2]octan-3-yl)-3-[3-(1h-indol-3-yl)-1-oxo-1-spiro[1,2-dihydroindene-3,4'-piperidine]-1'-ylpropan-2-yl]urea Chemical class C1N(CC2)CCC2C1NC(=O)NC(C(=O)N1CCC2(C3=CC=CC=C3CC2)CC1)CC1=CNC2=CC=CC=C12 JUXAVSAMVBLDKO-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 220
- 150000003839 salts Chemical class 0.000 claims abstract description 55
- 238000000034 method Methods 0.000 claims abstract description 36
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 42
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 27
- 238000011282 treatment Methods 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 238000002560 therapeutic procedure Methods 0.000 claims description 6
- 241000124008 Mammalia Species 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000008177 pharmaceutical agent Substances 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 67
- 238000002360 preparation method Methods 0.000 description 58
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 52
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
- 239000011541 reaction mixture Substances 0.000 description 51
- 239000000243 solution Substances 0.000 description 50
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- 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 32
- 235000019439 ethyl acetate Nutrition 0.000 description 30
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- -1 4-{[4- (1'H-spiro [inden-1,4'-piperidin] -1'-ylmethyl) benzyl] oxy} phenyl Chemical group 0.000 description 24
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- 238000003556 assay Methods 0.000 description 23
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 23
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- 229940125396 insulin Drugs 0.000 description 16
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- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 13
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- 239000000284 extract Substances 0.000 description 12
- 125000006239 protecting group Chemical group 0.000 description 11
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- 239000010452 phosphate Substances 0.000 description 10
- 239000002253 acid Chemical group 0.000 description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 9
- 230000002829 reductive effect Effects 0.000 description 9
- 229910052938 sodium sulfate Inorganic materials 0.000 description 9
- 235000011152 sodium sulphate Nutrition 0.000 description 9
- 0 **(C=C(CBr)C=C1)C=C1C(O*)=O Chemical compound **(C=C(CBr)C=C1)C=C1C(O*)=O 0.000 description 8
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 8
- 230000004913 activation Effects 0.000 description 8
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
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- 239000013058 crude material Substances 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 6
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
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- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 4
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- NRXVXFJZHGIWOZ-UHFFFAOYSA-N spiro[2h-indole-3,4'-piperidine]-1-carboxylic acid Chemical compound C12=CC=CC=C2N(C(=O)O)CC21CCNCC2 NRXVXFJZHGIWOZ-UHFFFAOYSA-N 0.000 description 1
- HMDCFJXXFDHNPR-UHFFFAOYSA-N spiro[indene-1,4'-piperidine];2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C1CNCCC21C1=CC=CC=C1C=C2 HMDCFJXXFDHNPR-UHFFFAOYSA-N 0.000 description 1
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- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/20—Spiro-condensed ring systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Diabetes (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Obesity (AREA)
- Endocrinology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Hematology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Emergency Medicine (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (4)
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|---|---|---|---|
| US25183909P | 2009-10-15 | 2009-10-15 | |
| US61/251,839 | 2009-10-15 | ||
| US30333410P | 2010-02-11 | 2010-02-11 | |
| US61/303,334 | 2010-02-11 |
Publications (1)
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|---|---|
| KR20120051777A true KR20120051777A (ko) | 2012-05-22 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020127009501A Ceased KR20120051777A (ko) | 2009-10-15 | 2010-10-11 | 스피로피페리딘 화합물 및 당뇨병의 치료를 위한 그의 제약 용도 |
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|---|---|
| US (1) | US8383642B2 (enExample) |
| EP (1) | EP2488500A1 (enExample) |
| JP (1) | JP2013508279A (enExample) |
| KR (1) | KR20120051777A (enExample) |
| CN (1) | CN102574807A (enExample) |
| AR (1) | AR078522A1 (enExample) |
| AU (1) | AU2010307094A1 (enExample) |
| BR (1) | BR112012008889A2 (enExample) |
| CA (1) | CA2777775A1 (enExample) |
| CL (1) | CL2012000921A1 (enExample) |
| CO (1) | CO6531458A2 (enExample) |
| CR (1) | CR20120177A (enExample) |
| DO (1) | DOP2012000105A (enExample) |
| EA (1) | EA201270560A1 (enExample) |
| EC (1) | ECSP12011799A (enExample) |
| IL (1) | IL218344A0 (enExample) |
| MA (1) | MA33662B1 (enExample) |
| MX (1) | MX2012004420A (enExample) |
| NZ (1) | NZ598972A (enExample) |
| PE (1) | PE20121437A1 (enExample) |
| PH (1) | PH12012500705A1 (enExample) |
| TN (1) | TN2012000152A1 (enExample) |
| TW (1) | TW201124415A (enExample) |
| WO (1) | WO2011046851A1 (enExample) |
| ZA (1) | ZA201202560B (enExample) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014171762A1 (ko) * | 2013-04-18 | 2014-10-23 | 현대약품 주식회사 | 신규한 3-(4-(벤질옥시)페닐)헥스-4-이노익 산 유도체, 이의 제조방법 및 이를 유효성분으로 함유하는 대사성 질환의 예방 또는 치료용 약학적 조성물 |
| WO2016060517A3 (ko) * | 2014-10-17 | 2016-09-15 | 현대약품 주식회사 | 신규한 3-(4- (벤질옥시)페닐)핵스- 4-이노익 산 유도체 및 다른 유효 성분을 포함하는 대사성 질환의 예방 또는 치료용 복합제제 |
Families Citing this family (25)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EA023857B1 (ru) | 2009-03-23 | 2016-07-29 | Гленмарк Фармасеутикалс С.А. | Сочлененные производные пиримидиндионов в качестве модуляторов trpa1 |
| SG174398A1 (en) | 2009-03-23 | 2011-10-28 | Glenmark Pharmaceuticals Sa | Furopyrimidinedione derivatives as trpa1 modulators |
| AR078948A1 (es) | 2009-11-30 | 2011-12-14 | Lilly Co Eli | Compuestos de espiropiperidina, composicion farmaceutica que lo comprenden y su uso para preparar un medicamento util para tratar la diabetes |
| PH12012501456A1 (en) | 2009-12-25 | 2012-10-29 | Mochida Pharm Co Ltd | Novel 3-hydroxy -5- arylisothiazole derivative |
| JP5809157B2 (ja) | 2010-10-08 | 2015-11-10 | 持田製薬株式会社 | 環状アミド誘導体 |
| US10973238B2 (en) | 2011-03-11 | 2021-04-13 | Intercontinental Great Brands Llc | System and method of forming multilayer confectionery |
| TW201247636A (en) | 2011-04-27 | 2012-12-01 | Mochida Pharm Co Ltd | Novel 3-hydroxyisothiazole 1-oxide derivatives |
| EP2716636A4 (en) | 2011-04-28 | 2014-11-26 | Mochida Pharm Co Ltd | CYCLIC AMIDE DERIVATIVE |
| AR087451A1 (es) * | 2011-08-17 | 2014-03-26 | Lilly Co Eli | Derivado de 1,2,3,4-tetrahidroquinolina util para tratamiento de diabetes |
| WO2013139341A1 (en) * | 2012-03-20 | 2013-09-26 | Syddansk Universitet | Gpr120 receptor modulators |
| WO2013185766A1 (en) * | 2012-06-15 | 2013-12-19 | Syddansk Universitet | Gpr120 receptor modulators |
| HUE032401T2 (en) | 2012-11-16 | 2017-09-28 | Bristol Myers Squibb Co | Dihydropyrazole GPR40 modulators |
| EP3068788A1 (en) | 2013-11-14 | 2016-09-21 | Cadila Healthcare Limited | Novel heterocyclic compounds |
| US20150351889A1 (en) | 2014-06-05 | 2015-12-10 | Vivex Biomedical Inc. | Dynamic Biometric Mesh |
| BR102018007822A2 (pt) | 2017-04-20 | 2018-11-06 | Gilead Sciences, Inc. | composto, métodos para inibir pd-1, pd-l1 e/ou interação de pd-1/pd-l1 e para tratamento de câncer, composição farmacêutica, e, kit para tratamento de ou prevenção de câncer ou uma doença ou condição |
| CN109666027A (zh) * | 2017-10-17 | 2019-04-23 | 中国科学院上海药物研究所 | 一类酰胺结构的gpr40激动剂化合物及其用途 |
| WO2019134984A1 (en) | 2018-01-08 | 2019-07-11 | Celon Pharma S.A. | 3-phenyl-4-hexynoic acid derivatives as gpr40 agonists |
| KR102708681B1 (ko) | 2018-02-13 | 2024-09-26 | 길리애드 사이언시즈, 인코포레이티드 | Pd-1/pd-l1 억제제 |
| EP4600247A3 (en) | 2018-04-19 | 2025-11-19 | Gilead Sciences, Inc. | Pd-1/pd-l1 inhibitors |
| UA126421C2 (uk) | 2018-07-13 | 2022-09-28 | Гіліад Сайєнсіз, Інк. | Інгібітори pd-1/pd-l1 |
| US11236085B2 (en) | 2018-10-24 | 2022-02-01 | Gilead Sciences, Inc. | PD-1/PD-L1 inhibitors |
| BR112022006546A2 (pt) | 2019-10-07 | 2022-08-30 | Kallyope Inc | Agonistas de gpr119 |
| CA3173731A1 (en) | 2020-02-28 | 2021-09-02 | Kallyope, Inc. | Gpr40 agonists |
| CN116323608A (zh) | 2020-05-19 | 2023-06-23 | 卡尔优普公司 | Ampk活化剂 |
| EP4172162A4 (en) | 2020-06-26 | 2024-08-07 | Kallyope, Inc. | AMPK ACTIVATORS |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK1385514T5 (da) * | 2001-04-18 | 2009-03-09 | Euro Celtique Sa | Spiroinden- og spiroindanforbindelser |
| AU2004227835B2 (en) * | 2003-04-04 | 2007-06-14 | Merck & Co., Inc. | Acylated spiropiperidine derivatives as melanocortin-4 receptor agonists |
| CA2544602A1 (en) * | 2003-11-04 | 2005-05-26 | Elixir Pharmaceuticals, Inc. | Therapeutic compounds and uses thereof |
| WO2005051890A1 (en) | 2003-11-19 | 2005-06-09 | Smithkline Beecham Corporation | Aminophenylcyclopropyl carboxylic acids and derivatives as agonists to gpr40 |
| EA011010B1 (ru) | 2004-02-27 | 2008-12-30 | Эмджен, Инк. | Соединения, модулирующие рецептор gpr40, фармацевтическая композиция, способ лечения заболеваний, чувствительных к модулированию рецептора gpr40 (варианты), способ модулирования функции gpr40 (варианты) и способ модулирования циркулирующей концентрации инсулина |
| EP2253315A1 (en) * | 2004-03-30 | 2010-11-24 | Takeda Pharmaceutical Company Limited | Alkoxyphenylpropanoic acid derivatives |
| EP1924546A1 (en) * | 2005-09-14 | 2008-05-28 | Amgen, Inc | Conformationally constrained 3- (4-hydroxy-phenyl) - substituted-propanoic acids useful for treating metabolic disorders |
| US7687526B2 (en) | 2006-09-07 | 2010-03-30 | Amgen Inc. | Benzo-fused compounds for use in treating metabolic disorders |
| ME02338B (me) | 2007-10-26 | 2013-02-28 | Japan Tobacco Inc | Spiro-ciklično jedinjenje i njegova upotreba u medicinske svrhe |
| ES2469824T3 (es) * | 2007-11-21 | 2014-06-20 | Janssen Pharmaceutica N.V. | Espiropiperidinas para su uso como inhibidores de la triptasa |
| AR078948A1 (es) | 2009-11-30 | 2011-12-14 | Lilly Co Eli | Compuestos de espiropiperidina, composicion farmaceutica que lo comprenden y su uso para preparar un medicamento util para tratar la diabetes |
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2010
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- 2010-10-06 TW TW099134098A patent/TW201124415A/zh unknown
- 2010-10-11 BR BR112012008889A patent/BR112012008889A2/pt not_active IP Right Cessation
- 2010-10-11 AU AU2010307094A patent/AU2010307094A1/en not_active Abandoned
- 2010-10-11 PE PE2012000492A patent/PE20121437A1/es not_active Application Discontinuation
- 2010-10-11 CN CN2010800462763A patent/CN102574807A/zh active Pending
- 2010-10-11 EA EA201270560A patent/EA201270560A1/ru unknown
- 2010-10-11 KR KR1020127009501A patent/KR20120051777A/ko not_active Ceased
- 2010-10-11 PH PH1/2012/500705A patent/PH12012500705A1/en unknown
- 2010-10-11 MX MX2012004420A patent/MX2012004420A/es not_active Application Discontinuation
- 2010-10-11 US US12/901,597 patent/US8383642B2/en not_active Expired - Fee Related
- 2010-10-11 EP EP10793349A patent/EP2488500A1/en not_active Withdrawn
- 2010-10-11 WO PCT/US2010/052126 patent/WO2011046851A1/en not_active Ceased
- 2010-10-11 CA CA2777775A patent/CA2777775A1/en not_active Abandoned
- 2010-10-11 JP JP2012534259A patent/JP2013508279A/ja not_active Withdrawn
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2012
- 2012-02-27 IL IL218344A patent/IL218344A0/en unknown
- 2012-04-02 TN TNP2012000152A patent/TN2012000152A1/en unknown
- 2012-04-09 MA MA34760A patent/MA33662B1/fr unknown
- 2012-04-10 ZA ZA2012/02560A patent/ZA201202560B/en unknown
- 2012-04-12 CR CR20120177A patent/CR20120177A/es not_active Application Discontinuation
- 2012-04-12 CL CL2012000921A patent/CL2012000921A1/es unknown
- 2012-04-13 EC ECSP12011799 patent/ECSP12011799A/es unknown
- 2012-04-13 DO DO2012000105A patent/DOP2012000105A/es unknown
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014171762A1 (ko) * | 2013-04-18 | 2014-10-23 | 현대약품 주식회사 | 신규한 3-(4-(벤질옥시)페닐)헥스-4-이노익 산 유도체, 이의 제조방법 및 이를 유효성분으로 함유하는 대사성 질환의 예방 또는 치료용 약학적 조성물 |
| CN105121423A (zh) * | 2013-04-18 | 2015-12-02 | 现代药品株式会社 | 新型3-(4-(苄氧基)苯基)己-4-炔酸衍生物、其制备方法、和包括其作为有效成分的用于预防和治疗代谢性疾病的药物组合物 |
| WO2016060517A3 (ko) * | 2014-10-17 | 2016-09-15 | 현대약품 주식회사 | 신규한 3-(4- (벤질옥시)페닐)핵스- 4-이노익 산 유도체 및 다른 유효 성분을 포함하는 대사성 질환의 예방 또는 치료용 복합제제 |
| AU2015331074B2 (en) * | 2014-10-17 | 2018-11-15 | Hyundai Pharm Co., Ltd. | Composite preparation, containing novel 3-(4-(benzyloxy)phenyl)hex-4-inoic acid derivative and another active ingredient, for preventing or treating metabolic diseases |
| US10821110B2 (en) | 2014-10-17 | 2020-11-03 | Hyundai Pharm Co., Ltd. | Composite preparation, containing novel 3-(4--(benzyloxy)phenyl)hex-4-inoic acid derivative and another active ingredient, for preventing or treating metabolic diseases |
Also Published As
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|---|---|
| ZA201202560B (en) | 2013-09-25 |
| MX2012004420A (es) | 2012-05-08 |
| IL218344A0 (en) | 2012-04-30 |
| PE20121437A1 (es) | 2012-10-26 |
| TW201124415A (en) | 2011-07-16 |
| TN2012000152A1 (en) | 2013-12-12 |
| JP2013508279A (ja) | 2013-03-07 |
| PH12012500705A1 (en) | 2012-10-29 |
| US20110092531A1 (en) | 2011-04-21 |
| AR078522A1 (es) | 2011-11-16 |
| NZ598972A (en) | 2013-06-28 |
| DOP2012000105A (es) | 2013-01-31 |
| BR112012008889A2 (pt) | 2019-09-24 |
| CL2012000921A1 (es) | 2012-09-14 |
| ECSP12011799A (es) | 2012-07-31 |
| CR20120177A (es) | 2012-06-06 |
| WO2011046851A1 (en) | 2011-04-21 |
| EP2488500A1 (en) | 2012-08-22 |
| AU2010307094A1 (en) | 2012-04-19 |
| CA2777775A1 (en) | 2011-04-21 |
| US8383642B2 (en) | 2013-02-26 |
| EA201270560A1 (ru) | 2012-09-28 |
| MA33662B1 (fr) | 2012-10-01 |
| CO6531458A2 (es) | 2012-09-28 |
| CN102574807A (zh) | 2012-07-11 |
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