BR112014016648B1 - derivados policíclicos, seus usos e seu processo de preparação, e composição farmacêutica - Google Patents
derivados policíclicos, seus usos e seu processo de preparação, e composição farmacêutica Download PDFInfo
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- BR112014016648B1 BR112014016648B1 BR112014016648-0A BR112014016648A BR112014016648B1 BR 112014016648 B1 BR112014016648 B1 BR 112014016648B1 BR 112014016648 A BR112014016648 A BR 112014016648A BR 112014016648 B1 BR112014016648 B1 BR 112014016648B1
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- alkyl
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 125000003367 polycyclic group Chemical group 0.000 title abstract description 16
- 239000003814 drug Substances 0.000 claims abstract description 16
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 15
- 229940079593 drug Drugs 0.000 claims abstract description 10
- 208000037265 diseases, disorders, signs and symptoms 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 6
- 229940125827 GPR40 agonist Drugs 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 176
- -1 cyan Chemical group 0.000 claims description 174
- 125000000623 heterocyclic group Chemical group 0.000 claims description 77
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 71
- 125000000217 alkyl group Chemical group 0.000 claims description 57
- 150000003839 salts Chemical class 0.000 claims description 55
- 125000001072 heteroaryl group Chemical group 0.000 claims description 48
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 42
- 229910052736 halogen Inorganic materials 0.000 claims description 36
- 150000002367 halogens Chemical group 0.000 claims description 36
- 102100026148 Free fatty acid receptor 1 Human genes 0.000 claims description 27
- 101000912510 Homo sapiens Free fatty acid receptor 1 Proteins 0.000 claims description 27
- 239000002904 solvent Substances 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 18
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 16
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 16
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 12
- 150000002431 hydrogen Chemical group 0.000 claims description 10
- 208000001145 Metabolic Syndrome Diseases 0.000 claims description 7
- 238000011282 treatment Methods 0.000 claims description 7
- 208000035475 disorder Diseases 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 230000002265 prevention Effects 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 16
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 8
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 6
- 125000005227 alkyl sulfonate group Chemical group 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 25
- 125000001424 substituent group Chemical group 0.000 abstract description 10
- 230000008569 process Effects 0.000 abstract description 2
- 229940124597 therapeutic agent Drugs 0.000 abstract description 2
- 201000010099 disease Diseases 0.000 abstract 1
- 208000030159 metabolic disease Diseases 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 231
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 150
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 144
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 134
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 102
- 238000006243 chemical reaction Methods 0.000 description 85
- 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 64
- 239000000706 filtrate Substances 0.000 description 61
- 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 60
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 56
- 239000002253 acid Substances 0.000 description 54
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 52
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 51
- 239000000203 mixture Substances 0.000 description 51
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 46
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 45
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 45
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 44
- 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
- 125000003118 aryl group Chemical group 0.000 description 38
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 37
- 239000007787 solid Substances 0.000 description 37
- 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
- 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 26
- 238000000746 purification Methods 0.000 description 25
- 229940022663 acetate Drugs 0.000 description 23
- 125000003545 alkoxy group Chemical group 0.000 description 22
- 238000005160 1H NMR spectroscopy Methods 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-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
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- 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 18
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 18
- 125000004432 carbon atom Chemical group C* 0.000 description 18
- 239000008103 glucose Substances 0.000 description 18
- 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 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
- 239000003513 alkali Substances 0.000 description 16
- 239000011541 reaction mixture Substances 0.000 description 16
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 15
- 229940125782 compound 2 Drugs 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
- 239000010802 sludge Substances 0.000 description 15
- 238000012360 testing method Methods 0.000 description 15
- 238000004809 thin layer chromatography Methods 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 13
- 239000011877 solvent mixture Substances 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
- 210000004027 cell Anatomy 0.000 description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 11
- 125000002619 bicyclic group Chemical group 0.000 description 11
- 210000004369 blood Anatomy 0.000 description 11
- 239000008280 blood Substances 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
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 description 10
- 235000011181 potassium carbonates Nutrition 0.000 description 10
- 235000011118 potassium hydroxide Nutrition 0.000 description 10
- 125000006413 ring segment Chemical group 0.000 description 10
- 102000004877 Insulin Human genes 0.000 description 9
- 108090001061 Insulin Proteins 0.000 description 9
- 241000700159 Rattus Species 0.000 description 9
- 229940125396 insulin Drugs 0.000 description 9
- 229910000029 sodium carbonate Inorganic materials 0.000 description 9
- 235000017550 sodium carbonate Nutrition 0.000 description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 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
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
- 239000000556 agonist Substances 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 7
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 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
- 125000000000 cycloalkoxy group Chemical group 0.000 description 6
- 125000005366 cycloalkylthio group Chemical group 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 125000005842 heteroatom Chemical group 0.000 description 6
- 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 6
- 125000002950 monocyclic group Chemical group 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 210000002381 plasma Anatomy 0.000 description 6
- 125000003396 thiol group Chemical group [H]S* 0.000 description 6
- 210000002237 B-cell of pancreatic islet Anatomy 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 241000699670 Mus sp. Species 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
- 150000002430 hydrocarbons Chemical group 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 description 5
- 239000012279 sodium borohydride Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 229910052717 sulfur Inorganic materials 0.000 description 5
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 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
- 239000012298 atmosphere Substances 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
- 238000010438 heat treatment Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 125000004435 hydrogen atom Chemical group [H]* 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
- 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
- 108020003175 receptors Proteins 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- 125000000547 substituted alkyl group Chemical group 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
- QPMSJEFZULFYTB-WCCKRBBISA-N (3s)-pyrrolidin-3-ol;hydrochloride Chemical compound Cl.O[C@H]1CCNC1 QPMSJEFZULFYTB-WCCKRBBISA-N 0.000 description 3
- GEQZTCMVWVDEDF-UHFFFAOYSA-N 2-cyanoacetyl chloride Chemical compound ClC(=O)CC#N GEQZTCMVWVDEDF-UHFFFAOYSA-N 0.000 description 3
- RGTRSFUXNGBZKU-UHFFFAOYSA-N 3-(4-hydroxy-2,6-dimethylphenyl)benzaldehyde Chemical compound CC1=CC(O)=CC(C)=C1C1=CC=CC(C=O)=C1 RGTRSFUXNGBZKU-UHFFFAOYSA-N 0.000 description 3
- UWDMKTDPDJCJOP-UHFFFAOYSA-N 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-ium-4-carboxylate Chemical compound CC1(C)CC(O)(C(O)=O)CC(C)(C)N1 UWDMKTDPDJCJOP-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 3
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 3
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 3
- 206010022489 Insulin Resistance Diseases 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 229940100389 Sulfonylurea Drugs 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- KHXQGLSTCGSGLW-RXMQYKEDSA-N [(3r)-oxolan-3-yl] methanesulfonate Chemical compound CS(=O)(=O)O[C@@H]1CCOC1 KHXQGLSTCGSGLW-RXMQYKEDSA-N 0.000 description 3
- NWBYDNXSPHICSZ-UHFFFAOYSA-N [3-(2,6-dimethyl-4-phenylmethoxyphenyl)-2-methylphenyl]methanol Chemical compound C=1C(C)=C(C=2C(=C(CO)C=CC=2)C)C(C)=CC=1OCC1=CC=CC=C1 NWBYDNXSPHICSZ-UHFFFAOYSA-N 0.000 description 3
- 230000003213 activating effect Effects 0.000 description 3
- 239000003472 antidiabetic agent Substances 0.000 description 3
- 125000004532 benzofuran-3-yl group Chemical group O1C=C(C2=C1C=CC=C2)* 0.000 description 3
- 229910001424 calcium ion Inorganic materials 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- XCIXKGXIYUWCLL-UHFFFAOYSA-N cyclopentanol Chemical compound OC1CCCC1 XCIXKGXIYUWCLL-UHFFFAOYSA-N 0.000 description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- KAQVFEITQMBSEF-UHFFFAOYSA-N cyclopentyl methanesulfonate Chemical compound CS(=O)(=O)OC1CCCC1 KAQVFEITQMBSEF-UHFFFAOYSA-N 0.000 description 3
- 125000001887 cyclopentyloxy group Chemical group C1(CCCC1)O* 0.000 description 3
- 235000014113 dietary fatty acids Nutrition 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- 229930195729 fatty acid Natural products 0.000 description 3
- 235000021588 free fatty acids Nutrition 0.000 description 3
- 235000009200 high fat diet Nutrition 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- 238000007410 oral glucose tolerance test Methods 0.000 description 3
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 3
- CUQOHAYJWVTKDE-UHFFFAOYSA-N potassium;butan-1-olate Chemical compound [K+].CCCC[O-] CUQOHAYJWVTKDE-UHFFFAOYSA-N 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
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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
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Diabetes (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Furan Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
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| 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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| 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 |
| 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 |
| US10968193B2 (en) | 2014-08-08 | 2021-04-06 | 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 |
| JP2017533981A (ja) | 2014-10-14 | 2017-11-16 | ビーエーエスエフ ソシエタス・ヨーロピアＢａｓｆ Ｓｅ | 香料としてのヘキサデカ−８，１５−ジエナールの使用 |
| 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 |
| 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 |
| 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 |
| 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 |
| TWI707849B (zh) | 2018-02-13 | 2020-10-21 | 美商基利科學股份有限公司 | Pd‐1/pd‐l1抑制劑 |
| KR102591947B1 (ko) | 2018-04-19 | 2023-10-25 | 길리애드 사이언시즈, 인코포레이티드 | Pd-1/pd-l1 억제제 |
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| IL295825A (en) | 2020-02-28 | 2022-10-01 | Kallyope Inc | gpr40 agonists |
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| 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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| 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 |
| AU2004309271A1 (en) * | 2003-12-25 | 2005-07-14 | Takeda Pharmaceutical Company Limited | 3-(4-benzyloxyphenyl)propanoic acid derivatives |
| US7786165B2 (en) | 2004-03-15 | 2010-08-31 | Takeda Pharmaceutical Company Limited | Aminophenylpropanoic acid derivative |
| US20060014785A1 (en) * | 2004-05-25 | 2006-01-19 | Metabolex, Inc. | Bicyclic, substituted triazoles as modulators of ppar and methods of their preparation |
| CA2646430A1 (en) * | 2006-03-14 | 2007-09-20 | Amgen Inc. | Bicyclic carboxylic acid derivatives useful for treating metabolic disorders |
| BRPI0713378A8 (pt) * | 2006-06-27 | 2018-01-02 | Takeda Pharmaceutical | composto, pró-droga, modulador da função do receptor gpr40, agente farmacêutico uso do composto, e, método de produção de uma forma opticamente ativa de um composto |
| NZ592603A (en) | 2008-10-21 | 2013-02-22 | 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. |
| SG173027A1 (en) | 2009-01-30 | 2011-08-29 | Toyama Chemical Co Ltd | N-acyl anthranilic acid derivative or salt thereof |
| EP2423176A4 (en) * | 2009-04-22 | 2012-11-07 | Astellas Pharma Inc | CARBOXYLIC ACID COMPOUND |
| WO2010143733A1 (en) * | 2009-06-09 | 2010-12-16 | 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 |
-
2012
- 2012-12-27 CN CN201280011690.XA patent/CN103429581B/zh active Active
- 2012-12-27 MX MX2014008125A patent/MX357780B/es active IP Right Grant
- 2012-12-27 US US14/371,123 patent/US9139548B2/en not_active Expired - Fee Related
- 2012-12-27 BR BR112014016648-0A patent/BR112014016648B1/pt not_active IP Right Cessation
- 2012-12-27 CA CA2860353A patent/CA2860353A1/en not_active Abandoned
- 2012-12-27 RU RU2014132158A patent/RU2621039C1/ru not_active IP Right Cessation
- 2012-12-27 JP JP2014551505A patent/JP6122871B2/ja active Active
- 2012-12-27 AU AU2012365706A patent/AU2012365706B2/en not_active Ceased
- 2012-12-27 WO PCT/CN2012/087606 patent/WO2013104257A1/zh not_active Ceased
- 2012-12-27 UA UAA201408867A patent/UA115975C2/uk unknown
- 2012-12-27 KR KR1020147022007A patent/KR102036547B1/ko not_active Expired - Fee Related
- 2012-12-27 EP EP12865081.9A patent/EP2803664B1/en not_active Not-in-force
-
2013
- 2013-01-09 TW TW102100678A patent/TWI588136B/zh not_active IP Right Cessation
-
2014
- 2014-06-24 ZA ZA2014/04625A patent/ZA201404625B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| KR20140117498A (ko) | 2014-10-07 |
| CA2860353A1 (en) | 2013-07-18 |
| CN103429581A (zh) | 2013-12-04 |
| MX357780B (es) | 2018-07-24 |
| BR112014016648A8 (pt) | 2017-07-04 |
| AU2012365706B2 (en) | 2015-08-20 |
| HK1188781A1 (zh) | 2014-05-16 |
| EP2803664B1 (en) | 2018-11-21 |
| AU2012365706A1 (en) | 2014-07-24 |
| UA115975C2 (uk) | 2018-01-25 |
| EP2803664A4 (en) | 2015-10-28 |
| JP2015503595A (ja) | 2015-02-02 |
| US9139548B2 (en) | 2015-09-22 |
| TWI588136B (zh) | 2017-06-21 |
| CN103429581B (zh) | 2015-08-26 |
| WO2013104257A1 (zh) | 2013-07-18 |
| US20150005282A1 (en) | 2015-01-01 |
| TW201329058A (zh) | 2013-07-16 |
| KR102036547B1 (ko) | 2019-10-25 |
| RU2621039C1 (ru) | 2017-05-31 |
| JP6122871B2 (ja) | 2017-04-26 |
| ZA201404625B (en) | 2015-11-25 |
| MX2014008125A (es) | 2014-09-22 |
| EP2803664A1 (en) | 2014-11-19 |
| BR112014016648A2 (pt) | 2017-06-13 |
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