JP5844355B2 - グルコキナーゼ活性剤としての３−オキソ−３，９−ジヒドロ−１Ｈ−クロメノ［２，３−ｃ］ピロール - Google Patents
グルコキナーゼ活性剤としての３−オキソ−３，９−ジヒドロ−１Ｈ−クロメノ［２，３−ｃ］ピロール Download PDFInfo
- Publication number
- JP5844355B2 JP5844355B2 JP2013514676A JP2013514676A JP5844355B2 JP 5844355 B2 JP5844355 B2 JP 5844355B2 JP 2013514676 A JP2013514676 A JP 2013514676A JP 2013514676 A JP2013514676 A JP 2013514676A JP 5844355 B2 JP5844355 B2 JP 5844355B2
- Authority
- JP
- Japan
- Prior art keywords
- dihydro
- oxo
- chromeno
- pyrrol
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- OMQSMMGQAKMWFJ-UHFFFAOYSA-N 2,9-dihydro-1h-chromeno[2,3-c]pyrrol-3-one Chemical compound O1C2=CC=CC=C2CC2=C1C(=O)NC2 OMQSMMGQAKMWFJ-UHFFFAOYSA-N 0.000 title 1
- 229940124828 glucokinase activator Drugs 0.000 title 1
- -1 —CH 2 -aryl Chemical group 0.000 claims description 466
- 150000001875 compounds Chemical class 0.000 claims description 214
- 239000000203 mixture Substances 0.000 claims description 58
- 238000000034 method Methods 0.000 claims description 54
- 125000000217 alkyl group Chemical group 0.000 claims description 41
- 150000003839 salts Chemical class 0.000 claims description 39
- 102000030595 Glucokinase Human genes 0.000 claims description 34
- 108010021582 Glucokinase Proteins 0.000 claims description 34
- 239000002253 acid Substances 0.000 claims description 34
- 125000001072 heteroaryl group Chemical group 0.000 claims description 31
- 229910052799 carbon Inorganic materials 0.000 claims description 27
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 24
- 238000011282 treatment Methods 0.000 claims description 22
- 125000003118 aryl group Chemical group 0.000 claims description 21
- 125000004432 carbon atom Chemical group C* 0.000 claims description 21
- 230000008569 process Effects 0.000 claims description 18
- 150000002148 esters Chemical class 0.000 claims description 17
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 16
- 208000030159 metabolic disease Diseases 0.000 claims description 16
- 229910052801 chlorine Inorganic materials 0.000 claims description 15
- 125000003277 amino group Chemical group 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical group 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 125000004076 pyridyl group Chemical group 0.000 claims description 12
- 125000005842 heteroatom Chemical group 0.000 claims description 11
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 10
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 10
- 125000000335 thiazolyl group Chemical group 0.000 claims description 10
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- CGSWQZWTNQZWNF-KRWDZBQOSA-N (2s)-n-(5-chloropyridin-2-yl)-2-(5,8-dimethoxy-3-oxo-1,9-dihydrochromeno[2,3-c]pyrrol-2-yl)-4-methylpentanamide Chemical compound O=C([C@H](CC(C)C)N1CC2=C(C1=O)OC=1C(OC)=CC=C(C=1C2)OC)NC1=CC=C(Cl)C=N1 CGSWQZWTNQZWNF-KRWDZBQOSA-N 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- GXNPIVLAMAOIGX-HNNXBMFYSA-N (2s)-2-(8-chloro-3-oxo-1,9-dihydrochromeno[2,3-c]pyrrol-2-yl)-4-methyl-n-(1,3-thiazol-2-yl)pentanamide Chemical compound O=C([C@@H](N1C(C2=C(CC3=C(Cl)C=CC=C3O2)C1)=O)CC(C)C)NC1=NC=CS1 GXNPIVLAMAOIGX-HNNXBMFYSA-N 0.000 claims description 5
- ZFITUKKMKFQVOV-HNNXBMFYSA-N (2s)-2-(8-methoxy-3-oxo-1,9-dihydrochromeno[2,3-c]pyrrol-2-yl)-4-methyl-n-(1,3-thiazol-2-yl)pentanamide Chemical compound O=C([C@H](CC(C)C)N1CC2=C(C1=O)OC=1C=CC=C(C=1C2)OC)NC1=NC=CS1 ZFITUKKMKFQVOV-HNNXBMFYSA-N 0.000 claims description 5
- 208000016097 disease of metabolism Diseases 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- ZGQKUSRLSNZSAZ-SFHVURJKSA-N (2s)-2-(5-chloro-3-oxo-1,9-dihydrochromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-n-(1,3-thiazol-2-yl)propanamide Chemical compound C([C@H](N1C(=O)C2=C(C1)CC=1C=CC=C(C=1O2)Cl)C(=O)NC=1SC=CN=1)C1CCCCC1 ZGQKUSRLSNZSAZ-SFHVURJKSA-N 0.000 claims description 4
- DDWDSGPCZOUOIV-FQEVSTJZSA-N (2s)-2-(5-chloro-3-oxo-1,9-dihydrochromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-n-pyridin-2-ylpropanamide Chemical compound C([C@H](N1C(=O)C2=C(C1)CC=1C=CC=C(C=1O2)Cl)C(=O)NC=1N=CC=CC=1)C1CCCCC1 DDWDSGPCZOUOIV-FQEVSTJZSA-N 0.000 claims description 4
- GAUIONMVLNGSKI-HNNXBMFYSA-N (2s)-2-(5-chloro-3-oxo-1,9-dihydrochromeno[2,3-c]pyrrol-2-yl)-4-methyl-n-(1,3-thiazol-2-yl)pentanamide Chemical compound O=C([C@@H](N1C(C2=C(CC3=CC=CC(Cl)=C3O2)C1)=O)CC(C)C)NC1=NC=CS1 GAUIONMVLNGSKI-HNNXBMFYSA-N 0.000 claims description 4
- YWKFGOWRGVXVRX-KRWDZBQOSA-N (2s)-2-(5-chloro-3-oxo-1,9-dihydrochromeno[2,3-c]pyrrol-2-yl)-4-methyl-n-pyridin-2-ylpentanamide Chemical compound O=C([C@@H](N1C(C2=C(CC3=CC=CC(Cl)=C3O2)C1)=O)CC(C)C)NC1=CC=CC=N1 YWKFGOWRGVXVRX-KRWDZBQOSA-N 0.000 claims description 4
- KODSXHNGZNXMHC-SFHVURJKSA-N (2s)-2-(8-chloro-3-oxo-1,9-dihydrochromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-n-(1,3-thiazol-2-yl)propanamide Chemical compound C([C@H](N1CC2=C(C1=O)OC=1C=CC=C(C=1C2)Cl)C(=O)NC=1SC=CN=1)C1CCCCC1 KODSXHNGZNXMHC-SFHVURJKSA-N 0.000 claims description 4
- WEEKKOREMIGRDV-FQEVSTJZSA-N (2s)-2-(8-chloro-3-oxo-1,9-dihydrochromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-n-pyridin-2-ylpropanamide Chemical compound C([C@H](N1CC2=C(C1=O)OC=1C=CC=C(C=1C2)Cl)C(=O)NC=1N=CC=CC=1)C1CCCCC1 WEEKKOREMIGRDV-FQEVSTJZSA-N 0.000 claims description 4
- FNNWHXSUOJRBJO-KRWDZBQOSA-N (2s)-2-(8-chloro-3-oxo-1,9-dihydrochromeno[2,3-c]pyrrol-2-yl)-4-methyl-n-pyridin-2-ylpentanamide Chemical compound O=C([C@@H](N1C(C2=C(CC3=C(Cl)C=CC=C3O2)C1)=O)CC(C)C)NC1=CC=CC=N1 FNNWHXSUOJRBJO-KRWDZBQOSA-N 0.000 claims description 4
- UCLWFNCLGOWCAZ-CTNGQTDRSA-N (2s)-3-cyclohexyl-n-[1-[(2r)-2,3-dihydroxypropyl]pyrazol-3-yl]-2-(8-methoxy-3-oxo-1,9-dihydrochromeno[2,3-c]pyrrol-2-yl)propanamide Chemical compound C([C@H](N1CC2=C(C1=O)OC=1C=CC=C(C=1C2)OC)C(=O)NC1=NN(C[C@@H](O)CO)C=C1)C1CCCCC1 UCLWFNCLGOWCAZ-CTNGQTDRSA-N 0.000 claims description 4
- QSWSHRPPPUYIDY-FQEVSTJZSA-N (2s)-n-(5-chloropyridin-2-yl)-3-cyclohexyl-2-(5,8-dimethoxy-3-oxo-1,9-dihydrochromeno[2,3-c]pyrrol-2-yl)propanamide Chemical compound C([C@H](N1CC2=C(C1=O)OC=1C(OC)=CC=C(C=1C2)OC)C(=O)NC=1N=CC(Cl)=CC=1)C1CCCCC1 QSWSHRPPPUYIDY-FQEVSTJZSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- USWJTLZIOPWSHR-SFHVURJKSA-N methyl 6-[[(2s)-2-(5,8-dimethoxy-3-oxo-1,9-dihydrochromeno[2,3-c]pyrrol-2-yl)-4-methylpentanoyl]amino]pyridine-3-carboxylate Chemical compound N1=CC(C(=O)OC)=CC=C1NC(=O)[C@H](CC(C)C)N1C(=O)C(OC=2C(=C(OC)C=CC=2OC)C2)=C2C1 USWJTLZIOPWSHR-SFHVURJKSA-N 0.000 claims description 4
- MPRPQSTVKHBSFO-SFHVURJKSA-N methyl 6-[[(2s)-2-(5-chloro-3-oxo-1,9-dihydrochromeno[2,3-c]pyrrol-2-yl)-4-methylpentanoyl]amino]pyridine-3-carboxylate Chemical compound N1=CC(C(=O)OC)=CC=C1NC(=O)[C@H](CC(C)C)N1C(=O)C(OC=2C(=CC=CC=2Cl)C2)=C2C1 MPRPQSTVKHBSFO-SFHVURJKSA-N 0.000 claims description 4
- FWJOQFXGWHNWCK-SFHVURJKSA-N methyl 6-[[(2s)-2-(8-chloro-3-oxo-1,9-dihydrochromeno[2,3-c]pyrrol-2-yl)-4-methylpentanoyl]amino]pyridine-3-carboxylate Chemical compound N1=CC(C(=O)OC)=CC=C1NC(=O)[C@H](CC(C)C)N1C(=O)C(OC=2C(=C(Cl)C=CC=2)C2)=C2C1 FWJOQFXGWHNWCK-SFHVURJKSA-N 0.000 claims description 4
- IKMJOSYSAQJYKR-NRFANRHFSA-N methyl 6-[[(2s)-3-cyclohexyl-2-(5,8-dimethoxy-3-oxo-1,9-dihydrochromeno[2,3-c]pyrrol-2-yl)propanoyl]amino]pyridine-3-carboxylate Chemical compound N1=CC(C(=O)OC)=CC=C1NC(=O)[C@@H](N1C(C2=C(CC3=C(OC)C=CC(OC)=C3O2)C1)=O)CC1CCCCC1 IKMJOSYSAQJYKR-NRFANRHFSA-N 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 4
- YCPFQYGGDDPZBJ-ZDUSSCGKSA-N (2s)-2-(5,8-dimethoxy-3-oxo-1,9-dihydrochromeno[2,3-c]pyrrol-2-yl)-4-methylpentanoic acid Chemical compound C1C=2C(OC)=CC=C(OC)C=2OC2=C1CN([C@@H](CC(C)C)C(O)=O)C2=O YCPFQYGGDDPZBJ-ZDUSSCGKSA-N 0.000 claims description 3
- OREFYHQAZOLNIE-SFHVURJKSA-N (2s)-3-cyclohexyl-2-(8-methoxy-3-oxo-1,9-dihydrochromeno[2,3-c]pyrrol-2-yl)-n-(1,3-thiazol-2-yl)propanamide Chemical compound C([C@H](N1CC2=C(C1=O)OC=1C=CC=C(C=1C2)OC)C(=O)NC=1SC=CN=1)C1CCCCC1 OREFYHQAZOLNIE-SFHVURJKSA-N 0.000 claims description 3
- UTYJLKOOXXNAFD-FQEVSTJZSA-N (2s)-3-cyclohexyl-2-(8-methoxy-3-oxo-1,9-dihydrochromeno[2,3-c]pyrrol-2-yl)-n-pyridin-2-ylpropanamide Chemical compound C([C@H](N1CC2=C(C1=O)OC=1C=CC=C(C=1C2)OC)C(=O)NC=1N=CC=CC=1)C1CCCCC1 UTYJLKOOXXNAFD-FQEVSTJZSA-N 0.000 claims description 3
- SOGPQIDCJBQCHY-FQEVSTJZSA-N (2s)-n-(5-chloropyridin-2-yl)-3-cyclohexyl-2-(8-methoxy-3-oxo-1,9-dihydrochromeno[2,3-c]pyrrol-2-yl)propanamide Chemical compound C([C@H](N1CC2=C(C1=O)OC=1C=CC=C(C=1C2)OC)C(=O)NC=1N=CC(Cl)=CC=1)C1CCCCC1 SOGPQIDCJBQCHY-FQEVSTJZSA-N 0.000 claims description 3
- BTGVPOVWLNJLLA-ZOWNYOTGSA-N ClC=1C=CC=NC1.ClC=1C=2CC3=C(C(N(C3)[C@H](C(=O)O)CC(C)C)=O)OC2C=CC1 Chemical compound ClC=1C=CC=NC1.ClC=1C=2CC3=C(C(N(C3)[C@H](C(=O)O)CC(C)C)=O)OC2C=CC1 BTGVPOVWLNJLLA-ZOWNYOTGSA-N 0.000 claims description 3
- 230000003213 activating effect Effects 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- AUQLZCWIYJYNOE-SFHVURJKSA-N methyl 6-[[(2s)-2-(8-methoxy-3-oxo-1,9-dihydrochromeno[2,3-c]pyrrol-2-yl)-4-methylpentanoyl]amino]pyridine-3-carboxylate Chemical compound N1=CC(C(=O)OC)=CC=C1NC(=O)[C@H](CC(C)C)N1C(=O)C(OC=2C(=C(OC)C=CC=2)C2)=C2C1 AUQLZCWIYJYNOE-SFHVURJKSA-N 0.000 claims description 3
- 150000004702 methyl esters Chemical class 0.000 claims description 3
- XRHQBOSYMFERIZ-SFHVURJKSA-N (2s)-3-cyclohexyl-2-(5,8-dimethoxy-3-oxo-1,9-dihydrochromeno[2,3-c]pyrrol-2-yl)-n-(1,3-thiazol-2-yl)propanamide Chemical compound C([C@H](N1CC2=C(C1=O)OC=1C(OC)=CC=C(C=1C2)OC)C(=O)NC=1SC=CN=1)C1CCCCC1 XRHQBOSYMFERIZ-SFHVURJKSA-N 0.000 claims description 2
- ZBTKODPNXRFMSF-FQEVSTJZSA-N (2s)-3-cyclohexyl-2-(5,8-dimethoxy-3-oxo-1,9-dihydrochromeno[2,3-c]pyrrol-2-yl)-n-pyridin-2-ylpropanamide Chemical compound C([C@H](N1CC2=C(C1=O)OC=1C(OC)=CC=C(C=1C2)OC)C(=O)NC=1N=CC=CC=1)C1CCCCC1 ZBTKODPNXRFMSF-FQEVSTJZSA-N 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 188
- 239000011541 reaction mixture Substances 0.000 description 81
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 75
- 239000000243 solution Substances 0.000 description 67
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 55
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 47
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 46
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 45
- 238000003818 flash chromatography Methods 0.000 description 43
- 239000007787 solid Substances 0.000 description 42
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 41
- 239000012044 organic layer Substances 0.000 description 41
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 37
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 33
- 238000006243 chemical reaction Methods 0.000 description 31
- 239000000741 silica gel Substances 0.000 description 31
- 229910002027 silica gel Inorganic materials 0.000 description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 30
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 27
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 27
- 238000010828 elution Methods 0.000 description 26
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 21
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 20
- 150000001299 aldehydes Chemical class 0.000 description 20
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 20
- 239000000460 chlorine Substances 0.000 description 19
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 18
- 235000001014 amino acid Nutrition 0.000 description 17
- 229940024606 amino acid Drugs 0.000 description 17
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 16
- 150000001413 amino acids Chemical class 0.000 description 16
- 239000012267 brine Substances 0.000 description 16
- 230000007935 neutral effect Effects 0.000 description 16
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 15
- 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 15
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 15
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 15
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 15
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 15
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 15
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 14
- 229940125904 compound 1 Drugs 0.000 description 14
- 239000003921 oil Substances 0.000 description 14
- 235000019198 oils Nutrition 0.000 description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 14
- 150000001721 carbon Chemical group 0.000 description 13
- 239000003480 eluent Substances 0.000 description 12
- 239000008103 glucose Substances 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000010410 layer Substances 0.000 description 11
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 10
- 230000002441 reversible effect Effects 0.000 description 10
- 125000001424 substituent group Chemical group 0.000 description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 9
- 239000003208 petroleum Substances 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 9
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 8
- 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 description 8
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 8
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 8
- 239000002808 molecular sieve Substances 0.000 description 8
- BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 description 8
- 229940080818 propionamide Drugs 0.000 description 8
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 8
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 8
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical compound NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 description 7
- MZRUFMBFIKGOAL-UHFFFAOYSA-N 5-nitro-1h-pyrazole Chemical compound [O-][N+](=O)C1=CC=NN1 MZRUFMBFIKGOAL-UHFFFAOYSA-N 0.000 description 7
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 7
- SLAMLWHELXOEJZ-UHFFFAOYSA-N 2-nitrobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1[N+]([O-])=O SLAMLWHELXOEJZ-UHFFFAOYSA-N 0.000 description 6
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000012190 activator Substances 0.000 description 6
- 125000003545 alkoxy group Chemical group 0.000 description 6
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 6
- SDGAEBKMHIPSAC-ONEGZZNKSA-N ethyl (e)-4-oxobut-2-enoate Chemical compound CCOC(=O)\C=C\C=O SDGAEBKMHIPSAC-ONEGZZNKSA-N 0.000 description 6
- CLFNIFXCXFIXTJ-UHFFFAOYSA-N ethyl 5-chloro-3-formyl-2h-chromene-2-carboxylate Chemical compound C1=CC(Cl)=C2C=C(C=O)C(C(=O)OCC)OC2=C1 CLFNIFXCXFIXTJ-UHFFFAOYSA-N 0.000 description 6
- JACPDLJUQLKABC-UHFFFAOYSA-N methyl 6-aminopyridine-3-carboxylate Chemical compound COC(=O)C1=CC=C(N)N=C1 JACPDLJUQLKABC-UHFFFAOYSA-N 0.000 description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
- 238000010561 standard procedure Methods 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 6
- 239000007821 HATU Substances 0.000 description 5
- 150000001298 alcohols Chemical class 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 239000011737 fluorine Substances 0.000 description 5
- 150000004820 halides Chemical class 0.000 description 5
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- 235000019341 magnesium sulphate Nutrition 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- MWBAXMBVZVFVNH-HNNXBMFYSA-N (2s)-2-[(5-chloro-2-formyl-4h-chromen-3-yl)methyl-methylamino]-4-methylpentanoic acid Chemical compound C1=CC(Cl)=C2CC(CN(C)[C@@H](CC(C)C)C(O)=O)=C(C=O)OC2=C1 MWBAXMBVZVFVNH-HNNXBMFYSA-N 0.000 description 4
- RKPPPKVKKAMZMQ-FQEVSTJZSA-N (2s)-3-cyclopentyl-n-[1-(2-hydroxy-2-methylpropyl)pyrazol-3-yl]-2-(3-oxo-1,9-dihydrochromeno[2,3-c]pyrrol-2-yl)propanamide Chemical compound CC(C)(O)CN1C=CC(NC(=O)[C@H](CC2CCCC2)N2C(C3=C(CC4=CC=CC=C4O3)C2)=O)=N1 RKPPPKVKKAMZMQ-FQEVSTJZSA-N 0.000 description 4
- KEEQSWOXTDTQJV-UHFFFAOYSA-N 4-hydroxyleucine Chemical class CC(C)(O)CC(N)C(O)=O KEEQSWOXTDTQJV-UHFFFAOYSA-N 0.000 description 4
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- MAXBVGJEFDMHNV-UHFFFAOYSA-N 5-chloropyridin-2-amine Chemical compound NC1=CC=C(Cl)C=N1 MAXBVGJEFDMHNV-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- 239000004471 Glycine Substances 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- IPWUCCSPVPSKOV-UHFFFAOYSA-N P(O)(O)=O.NCC(=O)O Chemical class P(O)(O)=O.NCC(=O)O IPWUCCSPVPSKOV-UHFFFAOYSA-N 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 150000003862 amino acid derivatives Chemical class 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 230000004153 glucose metabolism Effects 0.000 description 4
- 238000005984 hydrogenation reaction Methods 0.000 description 4
- 230000003914 insulin secretion Effects 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- XPEUJVMSARYTLS-VIFPVBQESA-N methyl (2s)-2-amino-3-cyclohexylpropanoate Chemical compound COC(=O)[C@@H](N)CC1CCCCC1 XPEUJVMSARYTLS-VIFPVBQESA-N 0.000 description 4
- QVDXUKJJGUSGLS-LURJTMIESA-N methyl L-leucinate Chemical compound COC(=O)[C@@H](N)CC(C)C QVDXUKJJGUSGLS-LURJTMIESA-N 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 150000003254 radicals Chemical class 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 4
- VIUCNIMDPZQXAD-UHFFFAOYSA-N 2-azaniumyl-4,4-difluorobutanoate Chemical compound OC(=O)C(N)CC(F)F VIUCNIMDPZQXAD-UHFFFAOYSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 3
- NJIVLHQRXZVQGM-NSHDSACASA-N ClC1=CC=CC=2CC3=C(C(N(C3)[C@@H](C)CC(C)C)=O)OC12 Chemical compound ClC1=CC=CC=2CC3=C(C(N(C3)[C@@H](C)CC(C)C)=O)OC12 NJIVLHQRXZVQGM-NSHDSACASA-N 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 102000005548 Hexokinase Human genes 0.000 description 3
- 108700040460 Hexokinases Proteins 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 150000001350 alkyl halides Chemical class 0.000 description 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 3
- 230000002152 alkylating effect Effects 0.000 description 3
- 230000029936 alkylation Effects 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 125000004619 benzopyranyl group Chemical group O1C(C=CC2=C1C=CC=C2)* 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 150000001649 bromium compounds Chemical class 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- PEVKVKTWYNOHLS-UHFFFAOYSA-N ethyl 3-formyl-2h-chromene-2-carboxylate Chemical class C1=CC=C2C=C(C=O)C(C(=O)OCC)OC2=C1 PEVKVKTWYNOHLS-UHFFFAOYSA-N 0.000 description 3
- VHPFVGPRWCGGAY-UHFFFAOYSA-N ethyl 3-formyl-5-methoxy-2h-chromene-2-carboxylate Chemical compound C1=CC(OC)=C2C=C(C=O)C(C(=O)OCC)OC2=C1 VHPFVGPRWCGGAY-UHFFFAOYSA-N 0.000 description 3
- OQIVZTSICVEVIA-ZQRQZVKFSA-N ethyl 5-chloro-3-[[[(2s)-3-cyclohexyl-1-methoxy-1-oxopropan-2-yl]amino]methyl]-2h-chromene-2-carboxylate Chemical compound C([C@H](NCC1=CC2=C(Cl)C=CC=C2OC1C(=O)OCC)C(=O)OC)C1CCCCC1 OQIVZTSICVEVIA-ZQRQZVKFSA-N 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 210000003494 hepatocyte Anatomy 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 125000004284 isoxazol-3-yl group Chemical group [H]C1=C([H])C(*)=NO1 0.000 description 3
- 235000005772 leucine Nutrition 0.000 description 3
- 150000002614 leucines Chemical class 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- JGMBUBVLEXLYEE-KKFHFHRHSA-N methyl (2s)-2-(8-chloro-3-oxo-1,3a-dihydrochromeno[2,3-c]pyrrol-2-yl)-3-cyclohexylpropanoate Chemical compound C([C@@H](C(=O)OC)N1C(C2OC3=CC=CC(Cl)=C3C=C2C1)=O)C1CCCCC1 JGMBUBVLEXLYEE-KKFHFHRHSA-N 0.000 description 3
- 125000002757 morpholinyl group Chemical group 0.000 description 3
- 150000002825 nitriles Chemical class 0.000 description 3
- 230000001590 oxidative effect Effects 0.000 description 3
- 150000002924 oxiranes Chemical class 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 125000004193 piperazinyl group Chemical group 0.000 description 3
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 description 3
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 3
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 3
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 2
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 2
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 2
- YIXHSXDYLWLVEC-HNNXBMFYSA-N (2s)-3-cyclopentyl-2-(3-oxo-1,9-dihydrochromeno[2,3-c]pyrrol-2-yl)propanoic acid Chemical compound C([C@@H](C(=O)O)N1C(C2=C(CC3=CC=CC=C3O2)C1)=O)C1CCCC1 YIXHSXDYLWLVEC-HNNXBMFYSA-N 0.000 description 2
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 2
- YQOLEILXOBUDMU-KRWDZBQOSA-N (4R)-5-[(6-bromo-3-methyl-2-pyrrolidin-1-ylquinoline-4-carbonyl)amino]-4-(2-chlorophenyl)pentanoic acid Chemical compound CC1=C(C2=C(C=CC(=C2)Br)N=C1N3CCCC3)C(=O)NC[C@H](CCC(=O)O)C4=CC=CC=C4Cl YQOLEILXOBUDMU-KRWDZBQOSA-N 0.000 description 2
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 2
- BGZGQDDKQNYZID-UHFFFAOYSA-N 1-(hydroxymethyl)cyclohexan-1-ol Chemical compound OCC1(O)CCCCC1 BGZGQDDKQNYZID-UHFFFAOYSA-N 0.000 description 2
- HBIQSLRAIUMVEV-UHFFFAOYSA-N 1-(hydroxymethyl)cyclopentan-1-ol Chemical compound OCC1(O)CCCC1 HBIQSLRAIUMVEV-UHFFFAOYSA-N 0.000 description 2
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 2
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 2
- GELKGHVAFRCJNA-UHFFFAOYSA-N 2,2-Dimethyloxirane Chemical compound CC1(C)CO1 GELKGHVAFRCJNA-UHFFFAOYSA-N 0.000 description 2
- NKULBUOBGILEAR-UHFFFAOYSA-N 2,2-difluoroethyl trifluoromethanesulfonate Chemical compound FC(F)COS(=O)(=O)C(F)(F)F NKULBUOBGILEAR-UHFFFAOYSA-N 0.000 description 2
- OJVAMHKKJGICOG-UHFFFAOYSA-N 2,5-hexanedione Chemical compound CC(=O)CCC(C)=O OJVAMHKKJGICOG-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- DGJTWBMINQYSMS-UHFFFAOYSA-N 2-amino-4,4-dichlorobutanoic acid Chemical compound OC(=O)C(N)CC(Cl)Cl DGJTWBMINQYSMS-UHFFFAOYSA-N 0.000 description 2
- HNZGXYVBLJPLTD-UHFFFAOYSA-N 2-amino-4,4-difluoropentanoic acid Chemical compound CC(F)(F)CC(N)C(O)=O HNZGXYVBLJPLTD-UHFFFAOYSA-N 0.000 description 2
- NPRYCHLHHVWLQZ-TURQNECASA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynylpurin-8-one Chemical compound NC1=NC=C2N(C(N(C2=N1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C NPRYCHLHHVWLQZ-TURQNECASA-N 0.000 description 2
- BGAJNPLDJJBRHK-UHFFFAOYSA-N 3-[2-[5-(3-chloro-4-propan-2-yloxyphenyl)-1,3,4-thiadiazol-2-yl]-3-methyl-6,7-dihydro-4h-pyrazolo[4,3-c]pyridin-5-yl]propanoic acid Chemical compound C1=C(Cl)C(OC(C)C)=CC=C1C1=NN=C(N2C(=C3CN(CCC(O)=O)CCC3=N2)C)S1 BGAJNPLDJJBRHK-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- 125000000972 4,5-dimethylthiazol-2-yl group Chemical group [H]C([H])([H])C1=C(N=C(*)S1)C([H])([H])[H] 0.000 description 2
- MBVFRSJFKMJRHA-UHFFFAOYSA-N 4-fluoro-1-benzofuran-7-carbaldehyde Chemical compound FC1=CC=C(C=O)C2=C1C=CO2 MBVFRSJFKMJRHA-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- WOZJFFYNTVKKRD-LBPRGKRZSA-N COC=1C=2CC3=C(C(N(C3)[C@@H](C)CC(C)C)=O)OC2C=CC1 Chemical compound COC=1C=2CC3=C(C(N(C3)[C@@H](C)CC(C)C)=O)OC2C=CC1 WOZJFFYNTVKKRD-LBPRGKRZSA-N 0.000 description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 2
- 229940126639 Compound 33 Drugs 0.000 description 2
- 229940127007 Compound 39 Drugs 0.000 description 2
- NBSCHQHZLSJFNQ-GASJEMHNSA-N D-Glucose 6-phosphate Chemical compound OC1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H](O)[C@H]1O NBSCHQHZLSJFNQ-GASJEMHNSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 101150109586 Gk gene Proteins 0.000 description 2
- VFRROHXSMXFLSN-UHFFFAOYSA-N Glc6P Natural products OP(=O)(O)OCC(O)C(O)C(O)C(O)C=O VFRROHXSMXFLSN-UHFFFAOYSA-N 0.000 description 2
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- PSLUFJFHTBIXMW-WYEYVKMPSA-N [(3r,4ar,5s,6s,6as,10s,10ar,10bs)-3-ethenyl-10,10b-dihydroxy-3,4a,7,7,10a-pentamethyl-1-oxo-6-(2-pyridin-2-ylethylcarbamoyloxy)-5,6,6a,8,9,10-hexahydro-2h-benzo[f]chromen-5-yl] acetate Chemical compound O([C@@H]1[C@@H]([C@]2(O[C@](C)(CC(=O)[C@]2(O)[C@@]2(C)[C@@H](O)CCC(C)(C)[C@@H]21)C=C)C)OC(=O)C)C(=O)NCCC1=CC=CC=N1 PSLUFJFHTBIXMW-WYEYVKMPSA-N 0.000 description 2
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 2
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 description 2
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 2
- 125000005197 alkyl carbonyloxy alkyl group Chemical group 0.000 description 2
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 description 2
- 125000004687 alkyl sulfinyl alkyl group Chemical group 0.000 description 2
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 2
- 125000006350 alkyl thio alkyl group Chemical group 0.000 description 2
- 125000004414 alkyl thio group Chemical group 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 150000001414 amino alcohols Chemical class 0.000 description 2
- 125000004103 aminoalkyl group Chemical group 0.000 description 2
- 125000005097 aminocarbonylalkyl group Chemical group 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000005099 aryl alkyl carbonyl group Chemical group 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 125000001769 aryl amino group Chemical group 0.000 description 2
- 125000005129 aryl carbonyl group Chemical group 0.000 description 2
- 125000005160 aryl oxy alkyl group Chemical group 0.000 description 2
- 125000005162 aryl oxy carbonyl amino group Chemical group 0.000 description 2
- 125000005135 aryl sulfinyl group Chemical group 0.000 description 2
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 2
- 125000005110 aryl thio group Chemical group 0.000 description 2
- 125000005164 aryl thioalkyl group Chemical group 0.000 description 2
- 125000004104 aryloxy group Chemical group 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 125000002393 azetidinyl group Chemical group 0.000 description 2
- 150000001540 azides Chemical class 0.000 description 2
- 125000004069 aziridinyl group Chemical group 0.000 description 2
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 2
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 2
- 125000004623 carbolinyl group Chemical group 0.000 description 2
- 125000005243 carbonyl alkyl group Chemical group 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 125000004181 carboxyalkyl group Chemical group 0.000 description 2
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 description 2
- 125000004230 chromenyl group Chemical group O1C(C=CC2=CC=CC=C12)* 0.000 description 2
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229940126142 compound 16 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125878 compound 36 Drugs 0.000 description 2
- 229940125807 compound 37 Drugs 0.000 description 2
- 229940126540 compound 41 Drugs 0.000 description 2
- 229940125844 compound 46 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 125000000332 coumarinyl group Chemical group O1C(=O)C(=CC2=CC=CC=C12)* 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 125000004966 cyanoalkyl group Chemical group 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- BHRYBJMEVXYODE-UHFFFAOYSA-N ethyl 3-(bromomethyl)-2h-chromene-2-carboxylate Chemical compound C1=CC=C2C=C(CBr)C(C(=O)OCC)OC2=C1 BHRYBJMEVXYODE-UHFFFAOYSA-N 0.000 description 2
- FWCKRPXJWGHTSL-UHFFFAOYSA-N ethyl 3-(hydroxymethyl)-2h-chromene-2-carboxylate Chemical compound C1=CC=C2C=C(CO)C(C(=O)OCC)OC2=C1 FWCKRPXJWGHTSL-UHFFFAOYSA-N 0.000 description 2
- ZLPMXHIUWCEOSI-YDNXMHBPSA-N ethyl 3-[[[(2s)-3-cyclohexyl-1-methoxy-1-oxopropan-2-yl]amino]methyl]-5-methoxy-2h-chromene-2-carboxylate Chemical compound C([C@H](NCC1=CC2=C(OC)C=CC=C2OC1C(=O)OCC)C(=O)OC)C1CCCCC1 ZLPMXHIUWCEOSI-YDNXMHBPSA-N 0.000 description 2
- PLZGNIDPWOXVFC-UHFFFAOYSA-N ethyl 3-formyl-5,8-dimethoxy-2h-chromene-2-carboxylate Chemical compound C1=CC(OC)=C2C=C(C=O)C(C(=O)OCC)OC2=C1OC PLZGNIDPWOXVFC-UHFFFAOYSA-N 0.000 description 2
- JWJLWGSJKGHTBD-UCFFOFKASA-N ethyl 5-methoxy-3-[[[(2s)-1-methoxy-4-methyl-1-oxopentan-2-yl]amino]methyl]-2h-chromene-2-carboxylate Chemical compound C1=CC(OC)=C2C=C(CN[C@@H](CC(C)C)C(=O)OC)C(C(=O)OCC)OC2=C1 JWJLWGSJKGHTBD-UCFFOFKASA-N 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000007429 general method Methods 0.000 description 2
- 230000014101 glucose homeostasis Effects 0.000 description 2
- 102000010705 glucose-6-phosphate dehydrogenase activity proteins Human genes 0.000 description 2
- 108040005050 glucose-6-phosphate dehydrogenase activity proteins Proteins 0.000 description 2
- 125000001188 haloalkyl group Chemical group 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 150000003944 halohydrins Chemical class 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 125000004634 hexahydroazepinyl group Chemical group N1(CCCCCC1)* 0.000 description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 2
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 description 2
- 125000002632 imidazolidinyl group Chemical group 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 2
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 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 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 0.000 description 2
- NNPPMTNAJDCUHE-UHFFFAOYSA-N isobutane Chemical compound CC(C)C NNPPMTNAJDCUHE-UHFFFAOYSA-N 0.000 description 2
- 125000003384 isochromanyl group Chemical group C1(OCCC2=CC=CC=C12)* 0.000 description 2
- 125000003151 isocoumarinyl group Chemical group C1(=O)OC(=CC2=CC=CC=C12)* 0.000 description 2
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 2
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 2
- 125000001786 isothiazolyl group Chemical group 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- RENRQMCACQEWFC-UGKGYDQZSA-N lnp023 Chemical compound C1([C@H]2N(CC=3C=4C=CNC=4C(C)=CC=3OC)CC[C@@H](C2)OCC)=CC=C(C(O)=O)C=C1 RENRQMCACQEWFC-UGKGYDQZSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- DQEUYIQDSMINEY-UHFFFAOYSA-M magnesium;prop-1-ene;bromide Chemical compound [Mg+2].[Br-].[CH2-]C=C DQEUYIQDSMINEY-UHFFFAOYSA-M 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 2
- BQRSBLSIUQYGAA-AWEZNQCLSA-N methyl (2s)-2-(5,8-dimethoxy-3-oxo-1,9-dihydrochromeno[2,3-c]pyrrol-2-yl)-4-methylpentanoate Chemical compound C1=CC(OC)=C2CC(CN(C3=O)[C@@H](CC(C)C)C(=O)OC)=C3OC2=C1OC BQRSBLSIUQYGAA-AWEZNQCLSA-N 0.000 description 2
- ZRIJCJGLEFAILM-AWEZNQCLSA-N methyl (2s)-2-(5-chloro-3-oxo-1,9-dihydrochromeno[2,3-c]pyrrol-2-yl)-4-methylpentanoate Chemical compound C1=CC=C2CC(CN(C3=O)[C@@H](CC(C)C)C(=O)OC)=C3OC2=C1Cl ZRIJCJGLEFAILM-AWEZNQCLSA-N 0.000 description 2
- OXOJFJDOZWZXJW-MBIQTGHCSA-N methyl (2s)-2-(8-methoxy-3-oxo-1,3a-dihydrochromeno[2,3-c]pyrrol-2-yl)-4-methylpentanoate Chemical compound C1=CC=C2OC(C(N([C@@H](CC(C)C)C(=O)OC)C3)=O)C3=CC2=C1OC OXOJFJDOZWZXJW-MBIQTGHCSA-N 0.000 description 2
- IJAKWZWACFSFOP-DIMJTDRSSA-N methyl (2s)-3-cyclohexyl-2-(8-methoxy-3-oxo-1,3a-dihydrochromeno[2,3-c]pyrrol-2-yl)propanoate Chemical compound C([C@@H](C(=O)OC)N1C(C2OC3=CC=CC(OC)=C3C=C2C1)=O)C1CCCCC1 IJAKWZWACFSFOP-DIMJTDRSSA-N 0.000 description 2
- INBMPMIWMNPLBZ-ATNAJCNCSA-N methyl (2s)-3-cyclopentyl-2-(3-oxo-1,3a-dihydrochromeno[2,3-c]pyrrol-2-yl)propanoate Chemical compound C([C@@H](C(=O)OC)N1C(C2OC3=CC=CC=C3C=C2C1)=O)C1CCCC1 INBMPMIWMNPLBZ-ATNAJCNCSA-N 0.000 description 2
- BERAQAOVKOIKIS-MYJWUSKBSA-N methyl 5-chloro-3-[[[(2s)-1-methoxy-4-methyl-1-oxopentan-2-yl]amino]methyl]-2h-chromene-2-carboxylate Chemical compound C1=CC=C2OC(C(=O)OC)C(CN[C@@H](CC(C)C)C(=O)OC)=CC2=C1Cl BERAQAOVKOIKIS-MYJWUSKBSA-N 0.000 description 2
- WCOCQFVTNJIJJN-HNNXBMFYSA-N methyl 5-chloro-3-[[[(2s)-1-methoxy-4-methyl-1-oxopentan-2-yl]amino]methyl]-4h-chromene-2-carboxylate Chemical compound C1=CC(Cl)=C2CC(CN[C@@H](CC(C)C)C(=O)OC)=C(C(=O)OC)OC2=C1 WCOCQFVTNJIJJN-HNNXBMFYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- HNBDRPTVWVGKBR-UHFFFAOYSA-N methyl pentanoate Chemical compound CCCCC(=O)OC HNBDRPTVWVGKBR-UHFFFAOYSA-N 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 125000001715 oxadiazolyl group Chemical group 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- 125000004287 oxazol-2-yl group Chemical group [H]C1=C([H])N=C(*)O1 0.000 description 2
- 125000002971 oxazolyl group Chemical group 0.000 description 2
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 2
- 125000005936 piperidyl group Chemical group 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 2
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 2
- 125000003373 pyrazinyl group Chemical group 0.000 description 2
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 2
- 125000002098 pyridazinyl group Chemical group 0.000 description 2
- 125000004590 pyridopyridyl group Chemical group N1=C(C=CC2=C1C=CC=N2)* 0.000 description 2
- 125000001422 pyrrolinyl group Chemical group 0.000 description 2
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- 125000004159 quinolin-2-yl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C([H])C(*)=NC2=C1[H] 0.000 description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 2
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- SMQUZDBALVYZAC-UHFFFAOYSA-N salicylaldehyde Chemical compound OC1=CC=CC=C1C=O SMQUZDBALVYZAC-UHFFFAOYSA-N 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000012258 stirred mixture Substances 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 150000003457 sulfones Chemical group 0.000 description 2
- 150000003462 sulfoxides Chemical group 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 2
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 2
- 125000001113 thiadiazolyl group Chemical group 0.000 description 2
- 125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 150000003568 thioethers Chemical group 0.000 description 2
- 150000003573 thiols Chemical group 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 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 2
- DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical group C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- HBSUMLZMJTZGBT-KRWDZBQOSA-N (2s)-2-(8-chloro-3-oxo-1,9-dihydrochromeno[2,3-c]pyrrol-2-yl)-n-(5-chloropyridin-2-yl)-4-methylpentanamide Chemical compound O=C([C@@H](N1C(C2=C(CC3=C(Cl)C=CC=C3O2)C1)=O)CC(C)C)NC1=CC=C(Cl)C=N1 HBSUMLZMJTZGBT-KRWDZBQOSA-N 0.000 description 1
- BURVSCKWRUZTPY-YFKPBYRVSA-N (2s)-2-(cyclobutylamino)propanoic acid Chemical compound OC(=O)[C@H](C)NC1CCC1 BURVSCKWRUZTPY-YFKPBYRVSA-N 0.000 description 1
- BVAUMRCGVHUWOZ-ZETCQYMHSA-N (2s)-2-(cyclohexylazaniumyl)propanoate Chemical compound OC(=O)[C@H](C)NC1CCCCC1 BVAUMRCGVHUWOZ-ZETCQYMHSA-N 0.000 description 1
- LDUWTIUXPVCEQF-LURJTMIESA-N (2s)-2-(cyclopentylamino)propanoic acid Chemical compound OC(=O)[C@H](C)NC1CCCC1 LDUWTIUXPVCEQF-LURJTMIESA-N 0.000 description 1
- RFOVYDPRGDZBLJ-QMMMGPOBSA-N (2s)-2-amino-3-(2,6-difluorophenyl)propanoic acid Chemical compound OC(=O)[C@@H](N)CC1=C(F)C=CC=C1F RFOVYDPRGDZBLJ-QMMMGPOBSA-N 0.000 description 1
- ITLNJMCHHMGMQM-INIZCTEOSA-N (2s)-3-cyclohexyl-2-(5,8-dimethoxy-3-oxo-1,9-dihydrochromeno[2,3-c]pyrrol-2-yl)propanoic acid Chemical compound C([C@H](N1CC2=C(C1=O)OC=1C(OC)=CC=C(C=1C2)OC)C(O)=O)C1CCCCC1 ITLNJMCHHMGMQM-INIZCTEOSA-N 0.000 description 1
- XIANJVFBSKULHC-INIZCTEOSA-N (2s)-3-cyclohexyl-2-(8-methoxy-3-oxo-1,9-dihydrochromeno[2,3-c]pyrrol-2-yl)propanoic acid Chemical compound C([C@H](N1CC2=C(C1=O)OC=1C=CC=C(C=1C2)OC)C(O)=O)C1CCCCC1 XIANJVFBSKULHC-INIZCTEOSA-N 0.000 description 1
- AOLOZWJKKMGWOZ-GGAORHGYSA-N (2s)-3-cyclohexyl-n-[1-[[(4r)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl]pyrazol-3-yl]-2-(8-methoxy-3-oxo-1,9-dihydrochromeno[2,3-c]pyrrol-2-yl)propanamide Chemical compound C([C@H](N1CC2=C(C1=O)OC=1C=CC=C(C=1C2)OC)C(=O)NC1=NN(C[C@H]2OC(C)(C)OC2)C=C1)C1CCCCC1 AOLOZWJKKMGWOZ-GGAORHGYSA-N 0.000 description 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 description 1
- JONIMGVUGJVFQD-UHFFFAOYSA-N (4-methylphenyl)sulfonylformonitrile Chemical compound CC1=CC=C(S(=O)(=O)C#N)C=C1 JONIMGVUGJVFQD-UHFFFAOYSA-N 0.000 description 1
- CTKINSOISVBQLD-GSVOUGTGSA-N (R)-Glycidol Chemical compound OC[C@@H]1CO1 CTKINSOISVBQLD-GSVOUGTGSA-N 0.000 description 1
- CTKINSOISVBQLD-VKHMYHEASA-N (S)-Glycidol Chemical compound OC[C@H]1CO1 CTKINSOISVBQLD-VKHMYHEASA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- KEIFWROAQVVDBN-UHFFFAOYSA-N 1,2-dihydronaphthalene Chemical compound C1=CC=C2C=CCCC2=C1 KEIFWROAQVVDBN-UHFFFAOYSA-N 0.000 description 1
- IGERFAHWSHDDHX-UHFFFAOYSA-N 1,3-dioxanyl Chemical group [CH]1OCCCO1 IGERFAHWSHDDHX-UHFFFAOYSA-N 0.000 description 1
- QTMFWQYTTCWLLT-UHFFFAOYSA-N 1-(3-aminopyrazol-1-yl)-2-methylpropan-2-ol Chemical compound CC(C)(O)CN1C=CC(N)=N1 QTMFWQYTTCWLLT-UHFFFAOYSA-N 0.000 description 1
- KTVGYAJQQQUOQX-UHFFFAOYSA-N 1-(hydroxymethyl)cyclobutan-1-ol Chemical compound OCC1(O)CCC1 KTVGYAJQQQUOQX-UHFFFAOYSA-N 0.000 description 1
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- OLGCGYLUNYDEOV-UHFFFAOYSA-N 1-hydroxycyclohexane-1-carbaldehyde Chemical compound O=CC1(O)CCCCC1 OLGCGYLUNYDEOV-UHFFFAOYSA-N 0.000 description 1
- AAHFAABFNIYXPY-UHFFFAOYSA-N 1-hydroxycyclopentane-1-carbaldehyde Chemical compound O=CC1(O)CCCC1 AAHFAABFNIYXPY-UHFFFAOYSA-N 0.000 description 1
- MOGQNVSKBCVIPW-UHFFFAOYSA-N 1-methylpyrazol-3-amine Chemical compound CN1C=CC(N)=N1 MOGQNVSKBCVIPW-UHFFFAOYSA-N 0.000 description 1
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- JVVRJMXHNUAPHW-UHFFFAOYSA-N 1h-pyrazol-5-amine Chemical compound NC=1C=CNN=1 JVVRJMXHNUAPHW-UHFFFAOYSA-N 0.000 description 1
- WLODWTPNUWYZKN-UHFFFAOYSA-N 1h-pyrrol-2-ol Chemical compound OC1=CC=CN1 WLODWTPNUWYZKN-UHFFFAOYSA-N 0.000 description 1
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 description 1
- OUYLXVQKVBXUGW-UHFFFAOYSA-N 2,3-dimethyl-1h-pyrrole Chemical group CC=1C=CNC=1C OUYLXVQKVBXUGW-UHFFFAOYSA-N 0.000 description 1
- OLKQIWCQICCYQS-UHFFFAOYSA-N 2-(4-methoxyphenyl)acetamide Chemical compound COC1=CC=C(CC(N)=O)C=C1 OLKQIWCQICCYQS-UHFFFAOYSA-N 0.000 description 1
- UXOCXYFPRHAXKM-UHFFFAOYSA-N 2-(8-methoxy-3-oxo-1,9-dihydrochromeno[2,3-c]pyrrol-2-yl)propanamide Chemical compound COC1=CC=CC2=C1CC1=C(C(N(C1)C(C(=O)N)C)=O)O2 UXOCXYFPRHAXKM-UHFFFAOYSA-N 0.000 description 1
- PYRKKGOKRMZEIT-UHFFFAOYSA-N 2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1h-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarbonitrile Chemical compound C1=C2C3=CC(CC(C)(O)C)=CC=C3C=3NC(C=4C(=CC(F)=CC=4C#N)C#N)=NC=3C2=CC=C1OCCC1CC1 PYRKKGOKRMZEIT-UHFFFAOYSA-N 0.000 description 1
- YZRGWMSKFDDWIE-UHFFFAOYSA-N 2-amino-3-(1,2-oxazol-5-yl)propanoic acid Chemical compound OC(=O)C(N)CC1=CC=NO1 YZRGWMSKFDDWIE-UHFFFAOYSA-N 0.000 description 1
- ZOWUSVBLJGQVRG-UHFFFAOYSA-N 2-amino-3-(1-fluorocyclobutyl)propanoic acid Chemical compound OC(=O)C(N)CC1(F)CCC1 ZOWUSVBLJGQVRG-UHFFFAOYSA-N 0.000 description 1
- ODNDRRRUIJWCIY-UHFFFAOYSA-N 2-amino-3-(1-fluorocyclohexyl)propanoic acid Chemical compound OC(=O)C(N)CC1(F)CCCCC1 ODNDRRRUIJWCIY-UHFFFAOYSA-N 0.000 description 1
- GBIUSBKVKIKNDL-UHFFFAOYSA-N 2-amino-3-(1-fluorocyclopentyl)propanoic acid Chemical compound OC(=O)C(N)CC1(F)CCCC1 GBIUSBKVKIKNDL-UHFFFAOYSA-N 0.000 description 1
- RVZXBOIDRZGICA-UHFFFAOYSA-N 2-amino-3-(1-hydroxycyclobutyl)propanoic acid Chemical compound OC(=O)C(N)CC1(O)CCC1 RVZXBOIDRZGICA-UHFFFAOYSA-N 0.000 description 1
- VWJMSHFUZLXTPR-UHFFFAOYSA-N 2-amino-3-(1-hydroxycyclopentyl)propanoic acid Chemical compound OC(=O)C(N)CC1(O)CCCC1 VWJMSHFUZLXTPR-UHFFFAOYSA-N 0.000 description 1
- VXXDNHDRHRMKSZ-UHFFFAOYSA-N 2-amino-3-(2-oxopyrrolidin-3-yl)propanoic acid Chemical compound OC(=O)C(N)CC1CCNC1=O VXXDNHDRHRMKSZ-UHFFFAOYSA-N 0.000 description 1
- XHRQGKXGXSRDQV-UHFFFAOYSA-N 2-amino-3-(oxan-2-yl)propanoic acid Chemical compound OC(=O)C(N)CC1CCCCO1 XHRQGKXGXSRDQV-UHFFFAOYSA-N 0.000 description 1
- JSHHRIISICNOLM-UHFFFAOYSA-N 2-amino-3-(oxan-4-yl)propanoic acid Chemical compound OC(=O)C(N)CC1CCOCC1 JSHHRIISICNOLM-UHFFFAOYSA-N 0.000 description 1
- CJBIBWYCBRWSOC-UHFFFAOYSA-N 2-amino-4-chloro-4-methylpentanoic acid Chemical compound CC(C)(Cl)CC(N)C(O)=O CJBIBWYCBRWSOC-UHFFFAOYSA-N 0.000 description 1
- UYFWXTAZASDCCA-UHFFFAOYSA-N 2-amino-4-fluoro-4-methylpentanoic acid Chemical compound CC(C)(F)CC(N)C(O)=O UYFWXTAZASDCCA-UHFFFAOYSA-N 0.000 description 1
- IMSUDXBVOIOXLR-UHFFFAOYSA-N 2-azaniumyl-3-(oxolan-2-yl)propanoate Chemical compound OC(=O)C(N)CC1CCCO1 IMSUDXBVOIOXLR-UHFFFAOYSA-N 0.000 description 1
- WTOFYLAWDLQMBZ-UHFFFAOYSA-N 2-azaniumyl-3-thiophen-2-ylpropanoate Chemical compound OC(=O)C(N)CC1=CC=CS1 WTOFYLAWDLQMBZ-UHFFFAOYSA-N 0.000 description 1
- JBKINHFZTVLNEM-UHFFFAOYSA-N 2-bromoethoxy-tert-butyl-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)OCCBr JBKINHFZTVLNEM-UHFFFAOYSA-N 0.000 description 1
- MVTWVXYIKIVAOJ-UHFFFAOYSA-N 2-chloro-6-hydroxybenzaldehyde Chemical compound OC1=CC=CC(Cl)=C1C=O MVTWVXYIKIVAOJ-UHFFFAOYSA-N 0.000 description 1
- 125000003006 2-dimethylaminoethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- HNVAGBIANFAIIL-UHFFFAOYSA-N 2-hydroxy-2-methylpropanal Chemical compound CC(C)(O)C=O HNVAGBIANFAIIL-UHFFFAOYSA-N 0.000 description 1
- TVMMXJBGOHHJBA-UHFFFAOYSA-N 2-hydroxy-3,6-dimethoxybenzaldehyde Chemical compound COC1=CC=C(OC)C(C=O)=C1O TVMMXJBGOHHJBA-UHFFFAOYSA-N 0.000 description 1
- DZJPDDVDKXHRLF-UHFFFAOYSA-N 2-hydroxy-6-methoxybenzaldehyde Chemical compound COC1=CC=CC(O)=C1C=O DZJPDDVDKXHRLF-UHFFFAOYSA-N 0.000 description 1
- QKPVEISEHYYHRH-UHFFFAOYSA-N 2-methoxyacetonitrile Chemical compound COCC#N QKPVEISEHYYHRH-UHFFFAOYSA-N 0.000 description 1
- BTVWZWFKMIUSGS-UHFFFAOYSA-N 2-methylpropane-1,2-diol Chemical compound CC(C)(O)CO BTVWZWFKMIUSGS-UHFFFAOYSA-N 0.000 description 1
- DOHOPUBZLWVZMZ-UHFFFAOYSA-N 3-chloro-2-hydroxybenzaldehyde Chemical compound OC1=C(Cl)C=CC=C1C=O DOHOPUBZLWVZMZ-UHFFFAOYSA-N 0.000 description 1
- OOWFYDWAMOKVSF-UHFFFAOYSA-N 3-methoxypropanenitrile Chemical compound COCCC#N OOWFYDWAMOKVSF-UHFFFAOYSA-N 0.000 description 1
- LDONGICLORXRIB-UHFFFAOYSA-N 4,4,4-trifluorobutanenitrile Chemical compound FC(F)(F)CCC#N LDONGICLORXRIB-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- ZLYBFBAHAQEEQQ-UHFFFAOYSA-N 4-chlorobenzenesulfonyl chloride Chemical compound ClC1=CC=C(S(Cl)(=O)=O)C=C1 ZLYBFBAHAQEEQQ-UHFFFAOYSA-N 0.000 description 1
- XFGVJLGVINCWDP-UHFFFAOYSA-N 5,5,5-trifluoroleucine Chemical compound FC(F)(F)C(C)CC(N)C(O)=O XFGVJLGVINCWDP-UHFFFAOYSA-N 0.000 description 1
- 125000004938 5-pyridyl group Chemical group N1=CC=CC(=C1)* 0.000 description 1
- JCBGSKLMUCBTJK-UHFFFAOYSA-N 5-trifluoromethyl-[1,3,4]thiadiazol-2-yl Chemical group FC(F)(F)C1=NN=[C]S1 JCBGSKLMUCBTJK-UHFFFAOYSA-N 0.000 description 1
- 102100031126 6-phosphogluconolactonase Human genes 0.000 description 1
- 108010029731 6-phosphogluconolactonase Proteins 0.000 description 1
- FYSCRDOEONWBCW-UHFFFAOYSA-N 7-bicyclo[2.2.1]heptanylmethanol Chemical compound C1CC2CCC1C2CO FYSCRDOEONWBCW-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 210000002237 B-cell of pancreatic islet Anatomy 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- YARRNRHVXMNGSS-UHFFFAOYSA-N C(=O)C=1C(OC2=C(C=CC(=C2C1)OC)OC)C(=O)O Chemical compound C(=O)C=1C(OC2=C(C=CC(=C2C1)OC)OC)C(=O)O YARRNRHVXMNGSS-UHFFFAOYSA-N 0.000 description 1
- FKBRKMHHBSVILQ-UHFFFAOYSA-N C(C)OC(C=1N=CC=NC1)([PH2]=O)C Chemical compound C(C)OC(C=1N=CC=NC1)([PH2]=O)C FKBRKMHHBSVILQ-UHFFFAOYSA-N 0.000 description 1
- NOLRZALLNWLUAA-UHFFFAOYSA-N CC(C)CC(C(Nc1ccccn1)=O)N(CC(C1)=C2Oc3c1c(OC)ccc3OC)C2=O Chemical compound CC(C)CC(C(Nc1ccccn1)=O)N(CC(C1)=C2Oc3c1c(OC)ccc3OC)C2=O NOLRZALLNWLUAA-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- GHOKWGTUZJEAQD-UHFFFAOYSA-N Chick antidermatitis factor Natural products OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- GACTWZZMVMUKNG-UHFFFAOYSA-N D-sorbitol phosphate Natural products OCC(O)C(O)C(O)C(O)COP(O)(O)=O GACTWZZMVMUKNG-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 108010018962 Glucosephosphate Dehydrogenase Proteins 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 102000005720 Glutathione transferase Human genes 0.000 description 1
- 108010070675 Glutathione transferase Proteins 0.000 description 1
- 102100023903 Glycerol kinase Human genes 0.000 description 1
- 229920002527 Glycogen Polymers 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241000192130 Leuconostoc mesenteroides Species 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- QXKHYNVANLEOEG-UHFFFAOYSA-N Methoxsalen Chemical group C1=CC(=O)OC2=C1C=C1C=COC1=C2OC QXKHYNVANLEOEG-UHFFFAOYSA-N 0.000 description 1
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- LGRFSURHDFAFJT-UHFFFAOYSA-N Phthalic anhydride Natural products C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 229920002684 Sepharose Polymers 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 description 1
- 125000005093 alkyl carbonyl alkyl group Chemical group 0.000 description 1
- 125000004688 alkyl sulfonyl alkyl group Chemical group 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 125000005100 aryl amino carbonyl group Chemical group 0.000 description 1
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000004190 benzothiazol-2-yl group Chemical group [H]C1=C([H])C([H])=C2N=C(*)SC2=C1[H] 0.000 description 1
- 125000004622 benzoxazinyl group Chemical group O1NC(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical compound CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940125877 compound 31 Drugs 0.000 description 1
- 229940127573 compound 38 Drugs 0.000 description 1
- 229940125936 compound 42 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 125000006310 cycloalkyl amino group Chemical group 0.000 description 1
- 125000004956 cyclohexylene group Chemical group 0.000 description 1
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 1
- KUYZGXUGKWWCFJ-UHFFFAOYSA-N cyclopentanone;methyl 4-methylbenzenesulfonate Chemical compound O=C1CCCC1.COS(=O)(=O)C1=CC=C(C)C=C1 KUYZGXUGKWWCFJ-UHFFFAOYSA-N 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 229960005215 dichloroacetic acid Drugs 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- 125000004982 dihaloalkyl group Chemical group 0.000 description 1
- OGCGXUGBDJGFFY-INIZCTEOSA-N diphenyl-[(2s)-pyrrolidin-2-yl]methanol Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(O)[C@@H]1CCCN1 OGCGXUGBDJGFFY-INIZCTEOSA-N 0.000 description 1
- GCSAXWHQFYOIFE-UHFFFAOYSA-N dipyridin-2-yl carbonate Chemical compound C=1C=CC=NC=1OC(=O)OC1=CC=CC=N1 GCSAXWHQFYOIFE-UHFFFAOYSA-N 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 125000005610 enamide group Chemical group 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- MJEBOMLXSMSDDI-LURJTMIESA-N ethyl (2s)-2-amino-4-fluoro-4-methylpentanoate Chemical compound CCOC(=O)[C@@H](N)CC(C)(C)F MJEBOMLXSMSDDI-LURJTMIESA-N 0.000 description 1
- OTOPEKSLBDWNEW-UCFFOFKASA-N ethyl 5,8-dimethoxy-3-[[[(2s)-1-methoxy-4-methyl-1-oxopentan-2-yl]amino]methyl]-2h-chromene-2-carboxylate Chemical compound C1=CC(OC)=C2C=C(CN[C@@H](CC(C)C)C(=O)OC)C(C(=O)OCC)OC2=C1OC OTOPEKSLBDWNEW-UCFFOFKASA-N 0.000 description 1
- 239000002038 ethyl acetate fraction Substances 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 230000009229 glucose formation Effects 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229940096919 glycogen Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229960000443 hydrochloric acid Drugs 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 230000003345 hyperglycaemic effect Effects 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 230000002262 irrigation Effects 0.000 description 1
- 238000003973 irrigation Methods 0.000 description 1
- 229940045996 isethionic acid Drugs 0.000 description 1
- 235000013847 iso-butane Nutrition 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004551 isoquinolin-3-yl group Chemical group C1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229960000448 lactic acid Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 230000004777 loss-of-function mutation Effects 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- OQQKJRKRLXOPLZ-MBIQTGHCSA-N methyl (2s)-2-(5,8-dimethoxy-3-oxo-1,3a-dihydrochromeno[2,3-c]pyrrol-2-yl)-4-methylpentanoate Chemical compound C1=CC(OC)=C2OC(C(N([C@@H](CC(C)C)C(=O)OC)C3)=O)C3=CC2=C1OC OQQKJRKRLXOPLZ-MBIQTGHCSA-N 0.000 description 1
- OFEUWMWPTDQYEM-KKFHFHRHSA-N methyl (2s)-2-(5-chloro-3-oxo-1,3a-dihydrochromeno[2,3-c]pyrrol-2-yl)-3-cyclohexylpropanoate Chemical compound C([C@@H](C(=O)OC)N1C(C2OC3=C(Cl)C=CC=C3C=C2C1)=O)C1CCCCC1 OFEUWMWPTDQYEM-KKFHFHRHSA-N 0.000 description 1
- NTYYREPXGNWWGJ-ATNAJCNCSA-N methyl (2s)-2-[(5-chloro-2-formyl-2h-chromen-3-yl)methyl-methylamino]-4-methylpentanoate Chemical compound C1=CC=C2OC(C=O)C(CN(C)[C@@H](CC(C)C)C(=O)OC)=CC2=C1Cl NTYYREPXGNWWGJ-ATNAJCNCSA-N 0.000 description 1
- JVQYFPUBCCPVFE-LBPRGKRZSA-N methyl (2s)-4-oxo-2-(phenylmethoxycarbonylamino)pentanoate Chemical compound COC(=O)[C@H](CC(C)=O)NC(=O)OCC1=CC=CC=C1 JVQYFPUBCCPVFE-LBPRGKRZSA-N 0.000 description 1
- VMVNZNXAVJHNDJ-UHFFFAOYSA-N methyl 2,2,2-trifluoroacetate Chemical compound COC(=O)C(F)(F)F VMVNZNXAVJHNDJ-UHFFFAOYSA-N 0.000 description 1
- WJVSKEPZGXDJEO-BUSXIPJBSA-N methyl 5,8-dimethoxy-3-[[[(2s)-1-methoxy-4-methyl-1-oxopentan-2-yl]amino]methyl]-2h-chromene-2-carboxylate Chemical compound C1=CC(OC)=C2OC(C(=O)OC)C(CN[C@@H](CC(C)C)C(=O)OC)=CC2=C1OC WJVSKEPZGXDJEO-BUSXIPJBSA-N 0.000 description 1
- CBFVIFQBLLCQSE-SFHVURJKSA-N methyl 5-chloro-3-[[[(2s)-3-cyclohexyl-1-methoxy-1-oxopropan-2-yl]amino]methyl]-4h-chromene-2-carboxylate Chemical compound C([C@@H](C(=O)OC)NCC=1CC2=C(Cl)C=CC=C2OC=1C(=O)OC)C1CCCCC1 CBFVIFQBLLCQSE-SFHVURJKSA-N 0.000 description 1
- ZVJNEVYUENZPOP-NRFANRHFSA-N methyl 6-[[(2s)-3-cyclohexyl-2-(8-methoxy-3-oxo-1,9-dihydrochromeno[2,3-c]pyrrol-2-yl)propanoyl]amino]pyridine-3-carboxylate Chemical compound N1=CC(C(=O)OC)=CC=C1NC(=O)[C@@H](N1C(C2=C(CC3=C(OC)C=CC=C3O2)C1)=O)CC1CCCCC1 ZVJNEVYUENZPOP-NRFANRHFSA-N 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical compound CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- PDUSWJORWQPNRP-UHFFFAOYSA-N n-propan-2-ylacetamide Chemical compound CC(C)NC(C)=O PDUSWJORWQPNRP-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
- BOPGDPNILDQYTO-NNYOXOHSSA-N nicotinamide-adenine dinucleotide Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 BOPGDPNILDQYTO-NNYOXOHSSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 238000007122 ortho-metalation reaction Methods 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 229940055726 pantothenic acid Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 210000004738 parenchymal cell Anatomy 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000005543 phthalimide group Chemical group 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 230000000291 postprandial effect Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- ZNNZYHKDIALBAK-UHFFFAOYSA-M potassium thiocyanate Chemical compound [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 description 1
- 229940116357 potassium thiocyanate Drugs 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000003138 primary alcohols Chemical class 0.000 description 1
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical compound F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical group O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000029964 regulation of glucose metabolic process Effects 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- MNOALXGAYUJNKX-UHFFFAOYSA-N s-chloro chloromethanethioate Chemical compound ClSC(Cl)=O MNOALXGAYUJNKX-UHFFFAOYSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- GACTWZZMVMUKNG-ZXXMMSQZSA-N sorbitol 6-phosphate Chemical compound OC[C@@H](O)[C@H](O)[C@@H](O)[C@H](O)COP(O)(O)=O GACTWZZMVMUKNG-ZXXMMSQZSA-N 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000004808 supercritical fluid chromatography Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- NLVXSWCKKBEXTG-UHFFFAOYSA-N vinylsulfonic acid Chemical compound OS(=O)(=O)C=C NLVXSWCKKBEXTG-UHFFFAOYSA-N 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
-
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- 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
-
- 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
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Diabetes (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US35561910P | 2010-06-17 | 2010-06-17 | |
| US61/355,619 | 2010-06-17 | ||
| PCT/EP2011/059783 WO2011157682A1 (en) | 2010-06-17 | 2011-06-14 | 3-oxo-3,9-dihydro-1h-chromeno[2,3-c]pyrroles as glucokinase activators |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2013532146A JP2013532146A (ja) | 2013-08-15 |
| JP2013532146A5 JP2013532146A5 (cg-RX-API-DMAC7.html) | 2014-07-31 |
| JP5844355B2 true JP5844355B2 (ja) | 2016-01-13 |
Family
ID=44266428
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2013514676A Expired - Fee Related JP5844355B2 (ja) | 2010-06-17 | 2011-06-14 | グルコキナーゼ活性剤としての３−オキソ−３，９−ジヒドロ−１Ｈ−クロメノ［２，３−ｃ］ピロール |
Country Status (10)
| Country | Link |
|---|---|
| US (1) | US8178689B2 (cg-RX-API-DMAC7.html) |
| EP (1) | EP2582706A1 (cg-RX-API-DMAC7.html) |
| JP (1) | JP5844355B2 (cg-RX-API-DMAC7.html) |
| KR (1) | KR20130120993A (cg-RX-API-DMAC7.html) |
| CN (1) | CN102947311B (cg-RX-API-DMAC7.html) |
| BR (1) | BR112012032235A2 (cg-RX-API-DMAC7.html) |
| CA (1) | CA2801168A1 (cg-RX-API-DMAC7.html) |
| MX (1) | MX2012010668A (cg-RX-API-DMAC7.html) |
| RU (1) | RU2603191C2 (cg-RX-API-DMAC7.html) |
| WO (1) | WO2011157682A1 (cg-RX-API-DMAC7.html) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NZ709362A (en) * | 2012-12-25 | 2019-07-26 | Hua Medicine | Process for the preparation of 1-([1,3]dioxolan-4-ylmethyl)-1h-pyrazol-3-ylamine |
| GB201714777D0 (en) | 2017-09-14 | 2017-11-01 | Univ London Queen Mary | Agent |
| CN112888480A (zh) * | 2018-10-24 | 2021-06-01 | 豪夫迈·罗氏有限公司 | 用于治疗和预防乙型肝炎病毒疾病的新型三环化合物 |
| CN113493442B (zh) * | 2020-04-03 | 2024-11-08 | 天津药物研究院有限公司 | 作为葡萄糖激酶活化剂的吡咯烷酮衍生物及其制备方法和用途 |
Family Cites Families (54)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0138622A3 (en) | 1983-10-18 | 1986-05-14 | E.I. Du Pont De Nemours And Company | 8-substituted pyrazolopentathiepins and related compounds |
| JPS6284064A (ja) | 1985-10-09 | 1987-04-17 | Shionogi & Co Ltd | ３−パ−フルオロアルキル−５−ヒドロキシイソオキサゾ−ル類 |
| JPH0477477A (ja) | 1990-07-18 | 1992-03-11 | Takeda Chem Ind Ltd | チアジアゾール酢酸誘導体の製造法 |
| GB9103454D0 (en) | 1991-02-19 | 1991-04-03 | Pfizer Ltd | Therapeutic agents |
| IL116507A (en) | 1991-11-13 | 1997-08-14 | Schering Ag | Pyrazole derivatives |
| US5498190A (en) | 1994-06-27 | 1996-03-12 | Handsontoys, Inc. | Flexible foam construction toy and method of manufacturing same |
| JPH08151386A (ja) | 1994-09-27 | 1996-06-11 | Takeda Chem Ind Ltd | 複素環エチルチオセフェム化合物、その製造法および抗菌組成物 |
| YU66000A (sh) | 1998-04-30 | 2003-12-31 | Agouron Pharmaceuticals Inc. | Antipikovirusna jedinjenja, njihovo dobijanje i upotreba |
| GB9812523D0 (en) | 1998-06-10 | 1998-08-05 | Angeletti P Ist Richerche Bio | Peptide inhibitors of hepatitis c virus ns3 protease |
| US6610846B1 (en) | 1999-03-29 | 2003-08-26 | Hoffman-La Roche Inc. | Heteroaromatic glucokinase activators |
| WO2001005783A1 (en) | 1999-07-15 | 2001-01-25 | Pharmacopeia, Inc. | Bradykinin b1 receptor antagonists |
| US7329679B2 (en) | 2000-01-27 | 2008-02-12 | Schering Aktiengesellschaft | 1,2 Diarylbenzimidazoles and their pharmaceutical use |
| KR100548901B1 (ko) | 2000-05-08 | 2006-02-02 | 에프. 호프만-라 로슈 아게 | 치환된 페닐아세트아미드 및 그의 글루코키나제활성화제로서의 용도 |
| US6482951B2 (en) * | 2000-12-13 | 2002-11-19 | Hoffmann-La Roche Inc. | Isoindolin-1-one glucokinase activators |
| GB0112834D0 (en) | 2001-05-25 | 2001-07-18 | Smithkline Beecham Plc | Medicaments |
| SE0102764D0 (sv) | 2001-08-17 | 2001-08-17 | Astrazeneca Ab | Compounds |
| AU2003232204B8 (en) | 2002-04-26 | 2009-07-30 | F. Hoffmann-La Roche Ag | Substituted phenylacetamides and their use as glucokinase activators |
| PL215132B1 (pl) | 2002-06-27 | 2013-10-31 | Novo Nordisk As | Pochodna arylokarbonylowa jako srodek terapeutyczny, jej zastosowanie i kompozycja farmaceutyczna ja zawierajaca |
| AU2003287038A1 (en) | 2002-10-09 | 2004-05-04 | The Board Of Trustees Of The University Of Illinois | METHOD OF PREPARING (3R, 3aS, 6aR) -3- HYDROXYHEXAHYDROFURO (2, 3-b) FURAN AND RELATED COMPOUNDS |
| MY141521A (en) | 2002-12-12 | 2010-05-14 | Hoffmann La Roche | 5-substituted-six-membered heteroaromatic glucokinase activators |
| PL378117A1 (pl) | 2003-02-11 | 2006-03-06 | Prosidion Limited | Tricyklopodstawione związki amidowe |
| BRPI0407283A (pt) | 2003-02-13 | 2006-01-31 | Banyu Pharma Co Ltd | Composto, composição farmacêutica, e, agente ativador de glucoquinase, agentes terapêuticos e/ou agentes preventivos para diabetes melito e obesidade |
| KR20050105488A (ko) | 2003-02-26 | 2005-11-04 | 반유 세이야꾸 가부시끼가이샤 | 헤테로아릴카바모일벤젠 유도체 |
| EP1682524A1 (en) | 2003-10-24 | 2006-07-26 | Aventis Pharmaceuticals, Inc. | Novel keto-oxadiazole derivatives as cathepsin inhibitors |
| JP4542550B2 (ja) | 2003-10-27 | 2010-09-15 | メルク・シャープ・エンド・ドーム・コーポレイション | Ｃｃｒ−２アンタゴニスト塩 |
| MXPA06007667A (es) | 2004-01-06 | 2006-09-01 | Novo Nordisk As | Heteroaril-ureas y su uso como activadores de glucocinasa. |
| CA2554686A1 (en) | 2004-02-18 | 2005-09-01 | Astrazeneca Ab | Compounds |
| EP1725523A4 (en) | 2004-03-16 | 2007-10-10 | Wyeth Corp | IONIC CHANNEL MODULATORS |
| AU2005223610B2 (en) | 2004-03-23 | 2008-05-29 | Banyu Pharmaceutical Co., Ltd. | Substituted quinazoline or pyridopyrimidine derivative |
| TW200600086A (en) | 2004-06-05 | 2006-01-01 | Astrazeneca Ab | Chemical compound |
| KR100672184B1 (ko) * | 2004-09-21 | 2007-01-19 | 주식회사종근당 | 파록세틴의 콜린산 또는 콜린산 유도체 염 |
| JP2008521864A (ja) | 2004-12-03 | 2008-06-26 | トランステック・ファーマ、インコーポレイテッド | ヘテロ芳香族グルコキナーゼ活性化剤 |
| WO2006064286A1 (en) | 2004-12-13 | 2006-06-22 | Medivir Uk Ltd | Cathepsin s inhibitors |
| JP2009500377A (ja) | 2005-07-08 | 2009-01-08 | ノボ・ノルデイスク・エー／エス | ジシクロアルキルウレア型グルコキナーゼ活性化剤 |
| KR100965040B1 (ko) | 2005-07-11 | 2010-06-21 | 미쓰비시 타나베 파마 코퍼레이션 | 옥심 유도체 및 그의 제조 방법 |
| CN101263131B (zh) | 2005-07-14 | 2013-04-24 | 特兰斯特克药品公司 | 脲葡糖激酶活化剂 |
| CA2621227A1 (en) | 2005-08-31 | 2007-03-08 | Astellas Pharma Inc. | Thiazole derivative |
| GT200600429A (es) | 2005-09-30 | 2007-04-30 | Compuestos organicos | |
| WO2007053503A1 (en) | 2005-11-01 | 2007-05-10 | Janssen Pharmaceutica N.V. | Substituted dihydroisoindolones as allosteric modulators of glucokinase |
| TWI411607B (zh) | 2005-11-14 | 2013-10-11 | Vitae Pharmaceuticals Inc | 天門冬胺酸蛋白酶抑制劑 |
| US20070197532A1 (en) | 2005-11-18 | 2007-08-23 | Cao Sheldon X | Glucokinase activators |
| JP5236499B2 (ja) | 2006-01-27 | 2013-07-17 | アレイ バイオファーマ、インコーポレイテッド | グルコキナーゼ活性化剤 |
| CA2647208C (en) | 2006-03-24 | 2014-05-13 | Array Biopharma Inc. | Glucokinase activators |
| WO2007115968A2 (en) | 2006-04-12 | 2007-10-18 | F. Hoffmann-La Roche Ag | Process for the preparation of a glucokinase activator |
| PT2463283E (pt) | 2006-04-20 | 2014-08-27 | Pfizer Prod Inc | Compostos heterocíclicos de fenil amido condensados para a prevenção e tratamento de doenças mediadas pela glucoquinase |
| EP2019824A2 (en) | 2006-04-28 | 2009-02-04 | Transtech Pharma, Inc. | Benzamide glucokinase activators |
| EP2049518B1 (en) | 2006-05-31 | 2011-08-31 | Takeda San Diego, Inc. | Indazole and isoindole derivatives as glucokinase activating agents. |
| US7910747B2 (en) | 2006-07-06 | 2011-03-22 | Bristol-Myers Squibb Company | Phosphonate and phosphinate pyrazolylamide glucokinase activators |
| CN101490064B (zh) * | 2006-07-06 | 2012-10-10 | 百时美施贵宝公司 | 新颖葡萄糖激酶活化剂及其使用方法 |
| US7888504B2 (en) | 2006-07-06 | 2011-02-15 | Bristol-Myers Squibb Company | Glucokinase activators and methods of using same |
| JP2009544648A (ja) | 2006-07-24 | 2009-12-17 | エフ．ホフマン−ラ ロシュ アーゲー | グルコキナーゼ活性化剤としてのピラゾール類 |
| WO2008111473A1 (ja) | 2007-03-07 | 2008-09-18 | Kyorin Pharmaceutical Co., Ltd. | グルコキナーゼ活性化物質 |
| WO2008121602A1 (en) | 2007-03-29 | 2008-10-09 | Smithkline Beecham Corporation | Chemical compounds |
| US7741327B2 (en) | 2008-04-16 | 2010-06-22 | Hoffmann-La Roche Inc. | Pyrrolidinone glucokinase activators |
-
2011
- 2011-06-09 US US13/156,394 patent/US8178689B2/en not_active Expired - Fee Related
- 2011-06-14 MX MX2012010668A patent/MX2012010668A/es active IP Right Grant
- 2011-06-14 RU RU2012156706/04A patent/RU2603191C2/ru not_active IP Right Cessation
- 2011-06-14 WO PCT/EP2011/059783 patent/WO2011157682A1/en not_active Ceased
- 2011-06-14 JP JP2013514676A patent/JP5844355B2/ja not_active Expired - Fee Related
- 2011-06-14 CN CN201180029732.8A patent/CN102947311B/zh not_active Expired - Fee Related
- 2011-06-14 CA CA2801168A patent/CA2801168A1/en not_active Abandoned
- 2011-06-14 KR KR1020127032727A patent/KR20130120993A/ko not_active Ceased
- 2011-06-14 BR BR112012032235A patent/BR112012032235A2/pt not_active IP Right Cessation
- 2011-06-14 EP EP11726127.1A patent/EP2582706A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| BR112012032235A2 (pt) | 2019-09-24 |
| KR20130120993A (ko) | 2013-11-05 |
| RU2012156706A (ru) | 2014-07-27 |
| CA2801168A1 (en) | 2011-12-22 |
| EP2582706A1 (en) | 2013-04-24 |
| US8178689B2 (en) | 2012-05-15 |
| JP2013532146A (ja) | 2013-08-15 |
| HK1178532A1 (zh) | 2013-09-13 |
| CN102947311B (zh) | 2015-11-25 |
| RU2603191C2 (ru) | 2016-11-27 |
| WO2011157682A1 (en) | 2011-12-22 |
| CN102947311A (zh) | 2013-02-27 |
| US20110313002A1 (en) | 2011-12-22 |
| MX2012010668A (es) | 2012-10-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5518838B2 (ja) | ピロリジノングルコキナーゼアクチベーター | |
| JP5301655B2 (ja) | ピリダジノングルコキナーゼアクチベーター | |
| JP2018526405A (ja) | ［｛［２，３−ジヒドロ−１Ｈ−インデン−１−イル］アミノ｝−２Ｈ，３Ｈ−フロ［３，２−ｂ］ピリジン−３−イル］酢酸、それらの医薬組成物および使用 | |
| EP3187492A1 (en) | Pyrimidinone derivative having autotaxin-inhibitory activity | |
| JP5844355B2 (ja) | グルコキナーゼ活性剤としての３−オキソ−３，９−ジヒドロ−１Ｈ−クロメノ［２，３−ｃ］ピロール | |
| AU2014352008B2 (en) | Tricyclic piperidine compounds | |
| US20130131113A1 (en) | Pyridone glucokinase activators | |
| HK1178532B (en) | 3-oxo-3,9-dihydro-1h-chromeno[2,3-c]pyrroles as glucokinase activators | |
| EP2880027B1 (en) | N-cyclopropyl-n-piperidinyl-amides, pharmaceutical compositions containing them and uses thereof | |
| US20120142705A1 (en) | Isatin and oxindole compounds | |
| US20230365551A1 (en) | Inhibitors of human respiratory syncytial virus and metapneumovirus | |
| KR20150064727A (ko) | 신규한 페닐아세트아미드 화합물 및 이를 함유하는 의약 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20140613 |
|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20140613 |
|
| RD04 | Notification of resignation of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7424 Effective date: 20150305 |
|
| A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20150423 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20150428 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20150724 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20151020 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20151118 |
|
| R150 | Certificate of patent or registration of utility model |
Ref document number: 5844355 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| LAPS | Cancellation because of no payment of annual fees |