RU2621039C1 - Полициклические производные, способ их получения и их фармацевтическое применение - Google Patents
Полициклические производные, способ их получения и их фармацевтическое применение Download PDFInfo
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- RU2621039C1 RU2621039C1 RU2014132158A RU2014132158A RU2621039C1 RU 2621039 C1 RU2621039 C1 RU 2621039C1 RU 2014132158 A RU2014132158 A RU 2014132158A RU 2014132158 A RU2014132158 A RU 2014132158A RU 2621039 C1 RU2621039 C1 RU 2621039C1
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- compound
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- formula
- cycloalkyl
- alkyl
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- 238000000034 method Methods 0.000 title claims abstract description 35
- 125000003367 polycyclic group Chemical group 0.000 title description 15
- 238000004519 manufacturing process Methods 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 151
- 239000000203 mixture Substances 0.000 claims abstract description 75
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 74
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 74
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 71
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 56
- 150000003839 salts Chemical class 0.000 claims abstract description 52
- 125000003118 aryl group Chemical group 0.000 claims abstract description 43
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 40
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 27
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 26
- 150000002367 halogens Chemical class 0.000 claims abstract description 25
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 24
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 17
- 239000001257 hydrogen Substances 0.000 claims abstract description 17
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 17
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 15
- 238000011282 treatment Methods 0.000 claims abstract description 10
- 208000001145 Metabolic Syndrome Diseases 0.000 claims abstract description 9
- 150000002431 hydrogen Chemical group 0.000 claims abstract description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 9
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims abstract description 7
- 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 abstract description 5
- 229940125827 GPR40 agonist Drugs 0.000 claims abstract description 5
- 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 claims abstract 7
- 239000002904 solvent Substances 0.000 claims description 35
- 102100026148 Free fatty acid receptor 1 Human genes 0.000 claims description 32
- 101000912510 Homo sapiens Free fatty acid receptor 1 Proteins 0.000 claims description 30
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 12
- 230000001105 regulatory effect Effects 0.000 claims description 5
- 230000002265 prevention Effects 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- 230000002964 excitative effect Effects 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 12
- 239000000126 substance Substances 0.000 abstract description 6
- 238000002360 preparation method Methods 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 abstract description 2
- 229940124597 therapeutic agent Drugs 0.000 abstract description 2
- 230000006806 disease prevention Effects 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 226
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 153
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 141
- -1 metformin Chemical compound 0.000 description 121
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 111
- 238000006243 chemical reaction Methods 0.000 description 87
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 78
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 66
- 238000004949 mass spectrometry Methods 0.000 description 66
- 239000000706 filtrate Substances 0.000 description 61
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 61
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 54
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 51
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 48
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 46
- 238000010828 elution Methods 0.000 description 44
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 43
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 42
- 239000007787 solid Substances 0.000 description 37
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
- 239000000284 extract Substances 0.000 description 33
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 30
- 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 30
- 238000010898 silica gel chromatography Methods 0.000 description 29
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 26
- 238000000746 purification Methods 0.000 description 24
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- 238000005481 NMR spectroscopy Methods 0.000 description 21
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 20
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 19
- 229910000024 caesium carbonate Inorganic materials 0.000 description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 18
- 239000012230 colorless oil Substances 0.000 description 17
- 235000011121 sodium hydroxide Nutrition 0.000 description 17
- 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
- 125000004432 carbon atom Chemical group C* 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
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
- 239000011541 reaction mixture Substances 0.000 description 16
- 239000007864 aqueous solution Substances 0.000 description 15
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 15
- 210000003097 mucus Anatomy 0.000 description 15
- 239000003921 oil Substances 0.000 description 15
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 15
- 229940125782 compound 2 Drugs 0.000 description 14
- 238000004809 thin layer chromatography Methods 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- 125000002619 bicyclic group Chemical group 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 11
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 10
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 10
- 210000004369 blood Anatomy 0.000 description 10
- 239000008280 blood Substances 0.000 description 10
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 10
- 235000011118 potassium hydroxide Nutrition 0.000 description 10
- 229910000029 sodium carbonate Inorganic materials 0.000 description 10
- 235000017550 sodium carbonate Nutrition 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 9
- 125000006413 ring segment Chemical group 0.000 description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 8
- 102000004877 Insulin Human genes 0.000 description 8
- 108090001061 Insulin Proteins 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- 229940125396 insulin Drugs 0.000 description 8
- RHMDISFJOKCCAQ-SSDOTTSWSA-N methyl 2-[(3s)-6-hydroxy-2,3-dihydro-1-benzofuran-3-yl]acetate Chemical compound OC1=CC=C2[C@H](CC(=O)OC)COC2=C1 RHMDISFJOKCCAQ-SSDOTTSWSA-N 0.000 description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 description 8
- 235000011181 potassium carbonates Nutrition 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 8
- 238000006467 substitution reaction Methods 0.000 description 8
- 241000700159 Rattus Species 0.000 description 7
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 6
- 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
- 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 6
- 125000000000 cycloalkoxy group Chemical group 0.000 description 6
- 125000005366 cycloalkylthio group Chemical group 0.000 description 6
- YFPCLQKFNXUAAK-UHFFFAOYSA-N cyclopentyl acetate Chemical compound CC(=O)OC1CCCC1 YFPCLQKFNXUAAK-UHFFFAOYSA-N 0.000 description 6
- 125000005842 heteroatom Chemical group 0.000 description 6
- 210000002381 plasma Anatomy 0.000 description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 description 6
- 239000012279 sodium borohydride Substances 0.000 description 6
- 125000003396 thiol group Chemical group [H]S* 0.000 description 6
- KHXQGLSTCGSGLW-RXMQYKEDSA-N [(3r)-oxolan-3-yl] methanesulfonate Chemical compound CS(=O)(=O)O[C@@H]1CCOC1 KHXQGLSTCGSGLW-RXMQYKEDSA-N 0.000 description 5
- 229940022663 acetate Drugs 0.000 description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 5
- 238000009833 condensation Methods 0.000 description 5
- 230000005494 condensation Effects 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 125000002950 monocyclic group Chemical group 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- 229910052717 sulfur Inorganic materials 0.000 description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- SJMXSAQJUSHNTI-SNVBAGLBSA-N (3r)-3-(4-bromo-3,5-dimethylphenoxy)oxolane Chemical compound CC1=C(Br)C(C)=CC(O[C@H]2COCC2)=C1 SJMXSAQJUSHNTI-SNVBAGLBSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 210000002237 B-cell of pancreatic islet Anatomy 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000000556 agonist Substances 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 239000012298 atmosphere Substances 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 4
- 150000002430 hydrocarbons Chemical group 0.000 description 4
- 230000003914 insulin secretion Effects 0.000 description 4
- 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 4
- WHQSYGRFZMUQGQ-UHFFFAOYSA-N n,n-dimethylformamide;hydrate Chemical compound O.CN(C)C=O WHQSYGRFZMUQGQ-UHFFFAOYSA-N 0.000 description 4
- 150000007530 organic bases Chemical class 0.000 description 4
- 239000011736 potassium bicarbonate Substances 0.000 description 4
- 235000015497 potassium bicarbonate Nutrition 0.000 description 4
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 4
- 239000012047 saturated solution Substances 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 4
- RPYNXFFOPNIXLU-SNVBAGLBSA-N (3R)-3-[4-bromo-3-(bromomethyl)-5-methylphenoxy]oxolane Chemical compound Cc1cc(O[C@@H]2CCOC2)cc(CBr)c1Br RPYNXFFOPNIXLU-SNVBAGLBSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 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 3
- OVLGKXVFZZXWIG-HSZRJFAPSA-N 2-[(3s)-6-[[3-(4-cyclopentyloxy-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=1OC1CCCC1 OVLGKXVFZZXWIG-HSZRJFAPSA-N 0.000 description 3
- BXRBLHYSAAROEO-XMMPIXPASA-N 2-[(3s)-6-[[3-[2,6-dimethyl-4-(1-methylsulfonylpiperidin-4-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=1OC1CCN(S(C)(=O)=O)CC1 BXRBLHYSAAROEO-XMMPIXPASA-N 0.000 description 3
- BBTGETRKFPWMMZ-HSZRJFAPSA-N 2-[(3s)-6-[[3-[2,6-dimethyl-4-(1-propanoylazetidin-3-yl)oxyphenyl]phenyl]methoxy]-2,3-dihydro-1-benzofuran-3-yl]acetic acid Chemical compound C1N(C(=O)CC)CC1OC1=CC(C)=C(C=2C=C(COC=3C=C4OC[C@@H](CC(O)=O)C4=CC=3)C=CC=2)C(C)=C1 BBTGETRKFPWMMZ-HSZRJFAPSA-N 0.000 description 3
- 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 3
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- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 description 1
- HBEDSQVIWPRPAY-UHFFFAOYSA-N dihydro-benzofuran Natural products C1=CC=C2OCCC2=C1 HBEDSQVIWPRPAY-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
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- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 238000007446 glucose tolerance test Methods 0.000 description 1
- 230000004190 glucose uptake Effects 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- MGXWVYUBJRZYPE-YUGYIWNOSA-N incretin Chemical class C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)[C@@H](C)O)[C@@H](C)CC)C1=CC=C(O)C=C1 MGXWVYUBJRZYPE-YUGYIWNOSA-N 0.000 description 1
- 239000000859 incretin Substances 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 210000002660 insulin-secreting cell Anatomy 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 229940049918 linoleate Drugs 0.000 description 1
- DTOSIQBPPRVQHS-PDBXOOCHSA-M linolenate Chemical compound CC\C=C/C\C=C/C\C=C/CCCCCCCC([O-])=O DTOSIQBPPRVQHS-PDBXOOCHSA-M 0.000 description 1
- 229940040452 linolenate Drugs 0.000 description 1
- 230000004132 lipogenesis Effects 0.000 description 1
- 238000012006 liquid chromatography with tandem mass spectrometry Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
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- ZWCXYZZRBTWJGB-AOYPEHQESA-N methyl 2-[(3S)-6-[[3-[2,6-dimethyl-4-[(3R)-1-methylsulfonylpyrrolidin-3-yl]oxyphenyl]phenyl]methoxy]-2,3-dihydro-1-benzofuran-3-yl]acetate Chemical compound COC(=O)C[C@@H]1COc2cc(OCc3cccc(c3)-c3c(C)cc(O[C@@H]4CCN(C4)S(C)(=O)=O)cc3C)ccc12 ZWCXYZZRBTWJGB-AOYPEHQESA-N 0.000 description 1
- COFDQLDRHQEHLV-RUZDIDTESA-N methyl 2-[(3S)-6-[[3-[4-[1-(cyclopropanecarbonyl)azetidin-3-yl]oxy-2,6-dimethylphenyl]phenyl]methoxy]-2,3-dihydro-1-benzofuran-3-yl]acetate Chemical compound COC(=O)C[C@@H]1COc2cc(OCc3cccc(c3)-c3c(C)cc(OC4CN(C4)C(=O)C4CC4)cc3C)ccc12 COFDQLDRHQEHLV-RUZDIDTESA-N 0.000 description 1
- MIFNUMWQYKGPGC-XMMPIXPASA-N methyl 2-[(3s)-6-[[3-(2,6-dimethyl-4-piperidin-4-yloxyphenyl)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=1C(C(=C1)C)=C(C)C=C1OC1CCNCC1 MIFNUMWQYKGPGC-XMMPIXPASA-N 0.000 description 1
- IKELWWMVMWZYAJ-RUZDIDTESA-N methyl 2-[(3s)-6-[[3-[2,6-dimethyl-4-(1-methylsulfonylpiperidin-4-yl)oxyphenyl]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=1C(C(=C1)C)=C(C)C=C1OC1CCN(S(C)(=O)=O)CC1 IKELWWMVMWZYAJ-RUZDIDTESA-N 0.000 description 1
- VKXXBNPSMUWZHL-NOZRDPDXSA-N methyl 2-[(3s)-6-[[3-[2,6-dimethyl-4-[(3s)-pyrrolidin-3-yl]oxyphenyl]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=1C(C(=C1)C)=C(C)C=C1O[C@H]1CCNC1 VKXXBNPSMUWZHL-NOZRDPDXSA-N 0.000 description 1
- ZSMPOIXXDVCSCN-AREMUKBSSA-N methyl 2-[(3s)-6-[[3-[4-(1-acetylpiperidin-4-yl)oxy-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=1C(C(=C1)C)=C(C)C=C1OC1CCN(C(C)=O)CC1 ZSMPOIXXDVCSCN-AREMUKBSSA-N 0.000 description 1
- URMMKZQNIXUODG-VPUSJEBWSA-N methyl 2-[(3s)-6-[[3-[4-[(3s)-1-acetylpyrrolidin-3-yl]oxy-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=1C(C(=C1)C)=C(C)C=C1O[C@H]1CCN(C(C)=O)C1 URMMKZQNIXUODG-VPUSJEBWSA-N 0.000 description 1
- JOSPEUKBLAYUBM-RUZDIDTESA-N methyl 2-[(3s)-6-[[3-[4-[tert-butyl(dimethyl)silyl]oxy-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[Si](C)(C)C(C)(C)C)C=C1C JOSPEUKBLAYUBM-RUZDIDTESA-N 0.000 description 1
- QNOFUBNFCQXHJQ-QPPBQGQZSA-N methyl 2-[(3s)-6-[[5-[2,6-dimethyl-4-[(3s)-oxolan-3-yl]oxyphenyl]-2-fluorophenyl]methoxy]-2,3-dihydro-1-benzofuran-3-yl]acetate Chemical compound C([C@H](C1=CC=2)CC(=O)OC)OC1=CC=2OCC(C(=CC=1)F)=CC=1C(C(=C1)C)=C(C)C=C1O[C@H]1CCOC1 QNOFUBNFCQXHJQ-QPPBQGQZSA-N 0.000 description 1
- RUZLIIJDZBWWSA-INIZCTEOSA-N methyl 2-[[(1s)-1-(7-methyl-2-morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino]benzoate Chemical group COC(=O)C1=CC=CC=C1N[C@@H](C)C1=CC(C)=CN2C(=O)C=C(N3CCOCC3)N=C12 RUZLIIJDZBWWSA-INIZCTEOSA-N 0.000 description 1
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- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
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- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
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- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 description 1
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
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- 239000002243 precursor Substances 0.000 description 1
- 201000009104 prediabetes syndrome Diseases 0.000 description 1
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- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
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- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- NYCVCXMSZNOGDH-UHFFFAOYSA-N pyrrolidine-1-carboxylic acid Chemical compound OC(=O)N1CCCC1 NYCVCXMSZNOGDH-UHFFFAOYSA-N 0.000 description 1
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- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- APCBTRDHCDOPNY-SSDOTTSWSA-N tert-butyl (3r)-3-hydroxypyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC[C@@H](O)C1 APCBTRDHCDOPNY-SSDOTTSWSA-N 0.000 description 1
- APCBTRDHCDOPNY-ZETCQYMHSA-N tert-butyl (3s)-3-hydroxypyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC[C@H](O)C1 APCBTRDHCDOPNY-ZETCQYMHSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 150000001467 thiazolidinediones Chemical class 0.000 description 1
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- 210000001519 tissue Anatomy 0.000 description 1
- LTEHWCSSIHAVOQ-UHFFFAOYSA-N tripropyl borate Chemical compound CCCOB(OCCC)OCCC LTEHWCSSIHAVOQ-UHFFFAOYSA-N 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
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
- 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
-
- 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
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)
- Furan Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (3)
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| CN201210008286.9 | 2012-01-12 | ||
| CN201210008286 | 2012-01-12 | ||
| PCT/CN2012/087606 WO2013104257A1 (zh) | 2012-01-12 | 2012-12-27 | 多环类衍生物、其制备方法及其在医药上的应用 |
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| RU2621039C1 true RU2621039C1 (ru) | 2017-05-31 |
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| EP (1) | EP2803664B1 (enExample) |
| JP (1) | JP6122871B2 (enExample) |
| KR (1) | KR102036547B1 (enExample) |
| CN (1) | CN103429581B (enExample) |
| AU (1) | AU2012365706B2 (enExample) |
| BR (1) | BR112014016648B1 (enExample) |
| CA (1) | CA2860353A1 (enExample) |
| MX (1) | MX357780B (enExample) |
| RU (1) | RU2621039C1 (enExample) |
| TW (1) | TWI588136B (enExample) |
| UA (1) | UA115975C2 (enExample) |
| WO (1) | WO2013104257A1 (enExample) |
| ZA (1) | ZA201404625B (enExample) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| RU2852177C1 (ru) * | 2020-09-10 | 2025-12-04 | Аб Фарма Лтд. | Бензокислородсодержащее гетероциклическое соединение и его применение в медицине |
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| CN104592211B (zh) * | 2013-10-31 | 2018-10-16 | 广东东阳光药业有限公司 | 联苯类化合物及其用途 |
| 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 |
| WO2016022742A1 (en) | 2014-08-08 | 2016-02-11 | Merck Sharp & Dohme Corp. | Antidiabetic bicyclic compounds |
| WO2016022446A1 (en) | 2014-08-08 | 2016-02-11 | Merck Sharp & Dohme Corp. | [5,6]-fused bicyclic antidiabetic compounds |
| WO2016019587A1 (en) | 2014-08-08 | 2016-02-11 | Merck Sharp & Dohme Corp. | [7, 6]-fused bicyclic antidiabetic compounds |
| US10662171B2 (en) | 2014-08-08 | 2020-05-26 | Merck Sharp & Dohme Corp. | Antidiabetic bicyclic compounds |
| US10087395B2 (en) | 2014-10-14 | 2018-10-02 | Basf Se | Use of hexadeca-8,15-dienal as aroma chemical |
| 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 |
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- 2012-12-27 US US14/371,123 patent/US9139548B2/en not_active Expired - Fee Related
- 2012-12-27 KR KR1020147022007A patent/KR102036547B1/ko not_active Expired - Fee Related
- 2012-12-27 RU RU2014132158A patent/RU2621039C1/ru not_active IP Right Cessation
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- 2012-12-27 MX MX2014008125A patent/MX357780B/es active IP Right Grant
- 2012-12-27 EP EP12865081.9A patent/EP2803664B1/en not_active Not-in-force
- 2012-12-27 CA CA2860353A patent/CA2860353A1/en not_active Abandoned
- 2012-12-27 UA UAA201408867A patent/UA115975C2/uk unknown
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Also Published As
| Publication number | Publication date |
|---|---|
| BR112014016648A8 (pt) | 2017-07-04 |
| KR20140117498A (ko) | 2014-10-07 |
| MX357780B (es) | 2018-07-24 |
| CA2860353A1 (en) | 2013-07-18 |
| AU2012365706B2 (en) | 2015-08-20 |
| BR112014016648A2 (pt) | 2017-06-13 |
| KR102036547B1 (ko) | 2019-10-25 |
| US20150005282A1 (en) | 2015-01-01 |
| JP2015503595A (ja) | 2015-02-02 |
| TW201329058A (zh) | 2013-07-16 |
| WO2013104257A1 (zh) | 2013-07-18 |
| HK1188781A1 (zh) | 2014-05-16 |
| AU2012365706A1 (en) | 2014-07-24 |
| UA115975C2 (uk) | 2018-01-25 |
| EP2803664B1 (en) | 2018-11-21 |
| MX2014008125A (es) | 2014-09-22 |
| EP2803664A1 (en) | 2014-11-19 |
| TWI588136B (zh) | 2017-06-21 |
| ZA201404625B (en) | 2015-11-25 |
| BR112014016648B1 (pt) | 2020-10-27 |
| US9139548B2 (en) | 2015-09-22 |
| CN103429581B (zh) | 2015-08-26 |
| EP2803664A4 (en) | 2015-10-28 |
| JP6122871B2 (ja) | 2017-04-26 |
| CN103429581A (zh) | 2013-12-04 |
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