SK8732003A3 - Isoindolin-1-one glucokinase activators - Google Patents
Isoindolin-1-one glucokinase activators Download PDFInfo
- Publication number
- SK8732003A3 SK8732003A3 SK873-2003A SK8732003A SK8732003A3 SK 8732003 A3 SK8732003 A3 SK 8732003A3 SK 8732003 A SK8732003 A SK 8732003A SK 8732003 A3 SK8732003 A3 SK 8732003A3
- Authority
- SK
- Slovakia
- Prior art keywords
- oxo
- cyclohexyl
- dihydro
- propionamide
- isoindol
- Prior art date
Links
- PXZQEOJJUGGUIB-UHFFFAOYSA-N isoindolin-1-one Chemical compound C1=CC=C2C(=O)NCC2=C1 PXZQEOJJUGGUIB-UHFFFAOYSA-N 0.000 title claims description 6
- 102000030595 Glucokinase Human genes 0.000 title abstract description 44
- 108010021582 Glucokinase Proteins 0.000 title abstract description 44
- 239000012190 activator Substances 0.000 title abstract description 15
- -1 Isoindolin-1-one-substituted propionamide Chemical class 0.000 claims abstract description 110
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 13
- 238000011282 treatment Methods 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 89
- 229940080818 propionamide Drugs 0.000 claims description 86
- 238000000034 method Methods 0.000 claims description 54
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 49
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 41
- 229910052799 carbon Inorganic materials 0.000 claims description 40
- 125000001072 heteroaryl group Chemical group 0.000 claims description 40
- 230000008878 coupling Effects 0.000 claims description 35
- 238000010168 coupling process Methods 0.000 claims description 35
- 238000005859 coupling reaction Methods 0.000 claims description 35
- 125000000217 alkyl group Chemical group 0.000 claims description 29
- 150000001721 carbon Chemical group 0.000 claims description 26
- 229910052757 nitrogen Chemical group 0.000 claims description 26
- 125000005843 halogen group Chemical group 0.000 claims description 20
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 15
- 125000005842 heteroatom Chemical group 0.000 claims description 13
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 13
- 229910052717 sulfur Inorganic materials 0.000 claims description 13
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 12
- 125000002950 monocyclic group Chemical group 0.000 claims description 12
- HAZJQNXTVYBGMP-QGZVFWFLSA-N (2r)-3-cyclohexyl-2-(3-oxo-1h-isoindol-2-yl)-n-(1,3-thiazol-2-yl)propanamide Chemical compound O=C([C@@H](CC1CCCCC1)N1C(C2=CC=CC=C2C1)=O)NC1=NC=CS1 HAZJQNXTVYBGMP-QGZVFWFLSA-N 0.000 claims description 11
- 125000004414 alkyl thio group Chemical group 0.000 claims description 11
- 150000001408 amides Chemical class 0.000 claims description 11
- 239000000460 chlorine Substances 0.000 claims description 11
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 10
- 239000011593 sulfur Substances 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- 125000003277 amino group Chemical group 0.000 claims description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 239000001301 oxygen Chemical group 0.000 claims description 8
- 125000004076 pyridyl group Chemical group 0.000 claims description 8
- 125000000335 thiazolyl group Chemical group 0.000 claims description 8
- 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 7
- 230000008569 process Effects 0.000 claims description 7
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 7
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 7
- 241001465754 Metazoa Species 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- VIPWGMMDZOTSGY-IBGZPJMESA-N (2s)-3-cyclohexyl-2-(3-oxo-1h-isoindol-2-yl)-n-pyridin-2-ylpropanamide Chemical compound O=C([C@H](CC1CCCCC1)N1C(C2=CC=CC=C2C1)=O)NC1=CC=CC=N1 VIPWGMMDZOTSGY-IBGZPJMESA-N 0.000 claims description 5
- 239000002671 adjuvant Substances 0.000 claims description 5
- 125000001246 bromo group Chemical group Br* 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 125000001153 fluoro group Chemical group F* 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- VPMSFNVPKXVXRA-UHFFFAOYSA-N n-(5-chloro-1,3-thiazol-2-yl)-3-cyclopentyl-2-(3-oxo-1h-isoindol-2-yl)propanamide Chemical compound S1C(Cl)=CN=C1NC(=O)C(N1C(C2=CC=CC=C2C1)=O)CC1CCCC1 VPMSFNVPKXVXRA-UHFFFAOYSA-N 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- AVZFDRVTBXTFED-LJQANCHMSA-N (2r)-n-(5-bromopyridin-2-yl)-3-cyclohexyl-2-(3-oxo-1h-isoindol-2-yl)propanamide Chemical compound N1=CC(Br)=CC=C1NC(=O)[C@H](N1C(C2=CC=CC=C2C1)=O)CC1CCCCC1 AVZFDRVTBXTFED-LJQANCHMSA-N 0.000 claims description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 150000002367 halogens Chemical group 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- SGQYBUJEJYXKCH-UHFFFAOYSA-N n-(1,3-thiazol-2-yl)propanamide Chemical compound CCC(=O)NC1=NC=CS1 SGQYBUJEJYXKCH-UHFFFAOYSA-N 0.000 claims description 4
- VEMZDALOYZQAEW-QHCPKHFHSA-N (2s)-3-cyclohexyl-2-(3-oxo-1h-isoindol-2-yl)-n-quinolin-2-ylpropanamide Chemical compound C([C@@H](C(NC=1N=C2C=CC=CC2=CC=1)=O)N1C(C2=CC=CC=C2C1)=O)C1CCCCC1 VEMZDALOYZQAEW-QHCPKHFHSA-N 0.000 claims description 3
- BVNOVXGXNDLFON-KRWDZBQOSA-N (2s)-3-cyclohexyl-2-(4-methylsulfonyl-3-oxo-1h-isoindol-2-yl)-n-pyrazin-2-ylpropanamide Chemical compound C([C@H](N1CC=2C=CC=C(C=2C1=O)S(=O)(=O)C)C(=O)NC=1N=CC=NC=1)C1CCCCC1 BVNOVXGXNDLFON-KRWDZBQOSA-N 0.000 claims description 3
- FSHQEAUMFQXYOM-SFHVURJKSA-N (2s)-3-cyclohexyl-2-(7-methylsulfonyl-3-oxo-1h-isoindol-2-yl)-n-pyrazin-2-ylpropanamide Chemical compound C([C@H](N1C(=O)C=2C=CC=C(C=2C1)S(=O)(=O)C)C(=O)NC=1N=CC=NC=1)C1CCCCC1 FSHQEAUMFQXYOM-SFHVURJKSA-N 0.000 claims description 3
- ABUMTHLKVAXGJG-SFHVURJKSA-N (2s)-3-cyclohexyl-2-(7-methylsulfonyl-3-oxo-1h-isoindol-2-yl)-n-pyrimidin-4-ylpropanamide Chemical compound C([C@H](N1C(=O)C=2C=CC=C(C=2C1)S(=O)(=O)C)C(=O)NC=1N=CN=CC=1)C1CCCCC1 ABUMTHLKVAXGJG-SFHVURJKSA-N 0.000 claims description 3
- HSVROUFTDPBEOI-FQEVSTJZSA-N (2s)-3-cyclohexyl-n-(4-methylpyridin-2-yl)-2-(3-oxo-1h-isoindol-2-yl)propanamide Chemical compound CC1=CC=NC(NC(=O)[C@H](CC2CCCCC2)N2C(C3=CC=CC=C3C2)=O)=C1 HSVROUFTDPBEOI-FQEVSTJZSA-N 0.000 claims description 3
- HEMJGYNZNHUXMQ-FQEVSTJZSA-N (2s)-n-(1,3-benzoxazol-2-yl)-3-cyclohexyl-2-(3-oxo-1h-isoindol-2-yl)propanamide Chemical compound C([C@@H](C(NC=1OC2=CC=CC=C2N=1)=O)N1C(C2=CC=CC=C2C1)=O)C1CCCCC1 HEMJGYNZNHUXMQ-FQEVSTJZSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 125000002883 imidazolyl group Chemical group 0.000 claims description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
- 238000011321 prophylaxis Methods 0.000 claims description 3
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 3
- 230000001225 therapeutic effect Effects 0.000 claims description 3
- FXJNEBZFBPOSTM-KRWDZBQOSA-N (2s)-3-cyclohexyl-2-(4-methylsulfonyl-3-oxo-1h-isoindol-2-yl)-n-pyrimidin-4-ylpropanamide Chemical compound C([C@H](N1CC=2C=CC=C(C=2C1=O)S(=O)(=O)C)C(=O)NC=1N=CN=CC=1)C1CCCCC1 FXJNEBZFBPOSTM-KRWDZBQOSA-N 0.000 claims description 2
- JKHHPJPIEXQNBA-FQEVSTJZSA-N (2s)-n-(1,3-benzothiazol-2-yl)-3-cyclohexyl-2-(3-oxo-1h-isoindol-2-yl)propanamide Chemical compound C([C@@H](C(NC=1SC2=CC=CC=C2N=1)=O)N1C(C2=CC=CC=C2C1)=O)C1CCCCC1 JKHHPJPIEXQNBA-FQEVSTJZSA-N 0.000 claims description 2
- JFZLHUCEJYRSNM-HNNXBMFYSA-N (2s)-n-(5-chloro-1,3-thiazol-2-yl)-3-cyclohexyl-2-(4-fluoro-3-oxo-1h-isoindol-2-yl)propanamide Chemical compound C([C@H](N1CC=2C=CC=C(C=2C1=O)F)C(=O)NC=1SC(Cl)=CN=1)C1CCCCC1 JFZLHUCEJYRSNM-HNNXBMFYSA-N 0.000 claims description 2
- XDZPUUOXMDFXIF-IBGZPJMESA-N (2s)-n-(5-chloropyridin-2-yl)-3-cyclohexyl-2-(3-oxo-1h-isoindol-2-yl)propanamide Chemical compound N1=CC(Cl)=CC=C1NC(=O)[C@@H](N1C(C2=CC=CC=C2C1)=O)CC1CCCCC1 XDZPUUOXMDFXIF-IBGZPJMESA-N 0.000 claims description 2
- PLENEAJJYFHWBP-HNNXBMFYSA-N (2s)-n-cyclohexyl-n-(2-methylpyrimidin-4-yl)-2-(3-oxo-1h-isoindol-2-yl)propanamide Chemical compound O=C([C@@H](N1C(C2=CC=CC=C2C1)=O)C)N(C=1N=C(C)N=CC=1)C1CCCCC1 PLENEAJJYFHWBP-HNNXBMFYSA-N 0.000 claims description 2
- MCSTZKDFCAKYAJ-UHFFFAOYSA-N 3-cyclohexyl-2-(3-oxo-1h-isoindol-2-yl)-n-pyrimidin-4-ylpropanamide Chemical compound C1CCCCC1CC(N1C(C2=CC=CC=C2C1)=O)C(=O)NC1=CC=NC=N1 MCSTZKDFCAKYAJ-UHFFFAOYSA-N 0.000 claims description 2
- BHGICAYVWJMPOK-UHFFFAOYSA-N 3-cyclooctyl-2-(3-oxo-1h-isoindol-2-yl)-n-(1,3-thiazol-2-yl)propanamide Chemical compound C1CCCCCCC1CC(N1C(C2=CC=CC=C2C1)=O)C(=O)NC1=NC=CS1 BHGICAYVWJMPOK-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 239000013543 active substance Substances 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- NSCIJCDEXRVCMK-UHFFFAOYSA-N n-(5-chloro-1,3-thiazol-2-yl)-3-cycloheptyl-2-(3-oxo-1h-isoindol-2-yl)propanamide Chemical compound S1C(Cl)=CN=C1NC(=O)C(N1C(C2=CC=CC=C2C1)=O)CC1CCCCCC1 NSCIJCDEXRVCMK-UHFFFAOYSA-N 0.000 claims description 2
- 230000000069 prophylactic effect Effects 0.000 claims description 2
- AESJIZQMLZJCIX-KRWDZBQOSA-N (2s)-3-cyclohexyl-2-(4-fluoro-3-oxo-1h-isoindol-2-yl)-n-pyrazin-2-ylpropanamide Chemical compound C([C@H](N1CC=2C=CC=C(C=2C1=O)F)C(=O)NC=1N=CC=NC=1)C1CCCCC1 AESJIZQMLZJCIX-KRWDZBQOSA-N 0.000 claims 1
- PIINXYKJQGMIOZ-UHFFFAOYSA-N 1,2-dipyridin-2-ylethane-1,2-dione Chemical compound C=1C=CC=NC=1C(=O)C(=O)C1=CC=CC=N1 PIINXYKJQGMIOZ-UHFFFAOYSA-N 0.000 claims 1
- 238000010976 amide bond formation reaction Methods 0.000 claims 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims 1
- 230000003914 insulin secretion Effects 0.000 abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 135
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 88
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 84
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 84
- 239000000203 mixture Substances 0.000 description 78
- 239000000243 solution Substances 0.000 description 61
- 239000003480 eluent Substances 0.000 description 35
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 28
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 27
- 239000007787 solid Substances 0.000 description 27
- 238000003818 flash chromatography Methods 0.000 description 23
- 239000002253 acid Substances 0.000 description 22
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 20
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 18
- 239000006260 foam Substances 0.000 description 18
- 238000010992 reflux Methods 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 17
- 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 17
- GEKUFTBQNVFPHS-HNNXBMFYSA-N (2s)-3-cyclohexyl-2-(3-oxo-1h-isoindol-2-yl)propanoic acid Chemical compound C([C@@H](C(=O)O)N1C(C2=CC=CC=C2C1)=O)C1CCCCC1 GEKUFTBQNVFPHS-HNNXBMFYSA-N 0.000 description 16
- HAZJQNXTVYBGMP-KRWDZBQOSA-N (2s)-3-cyclohexyl-2-(3-oxo-1h-isoindol-2-yl)-n-(1,3-thiazol-2-yl)propanamide Chemical compound O=C([C@H](CC1CCCCC1)N1C(C2=CC=CC=C2C1)=O)NC1=NC=CS1 HAZJQNXTVYBGMP-KRWDZBQOSA-N 0.000 description 15
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Chemical group CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- 239000008103 glucose Substances 0.000 description 15
- 229910052938 sodium sulfate Inorganic materials 0.000 description 15
- 235000011152 sodium sulphate Nutrition 0.000 description 15
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 14
- 239000000284 extract Substances 0.000 description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 150000001412 amines Chemical class 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 150000002148 esters Chemical class 0.000 description 11
- 239000011734 sodium Substances 0.000 description 11
- 239000012267 brine Substances 0.000 description 10
- 238000004587 chromatography analysis Methods 0.000 description 10
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 229910052786 argon Inorganic materials 0.000 description 9
- XNGIFLGASWRNHJ-UHFFFAOYSA-N o-dicarboxybenzene Natural products OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 9
- 239000012043 crude product Substances 0.000 description 8
- 239000008280 blood Substances 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 235000019198 oils Nutrition 0.000 description 7
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 6
- GTMGFQYVLSQTKP-UHFFFAOYSA-N 5-chloro-1,3-thiazol-3-ium-2-amine;chloride Chemical compound Cl.NC1=NC=C(Cl)S1 GTMGFQYVLSQTKP-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 230000004071 biological effect Effects 0.000 description 6
- BJDCWCLMFKKGEE-CMDXXVQNSA-N chembl252518 Chemical compound C([C@@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@H](O)[C@@H]4C BJDCWCLMFKKGEE-CMDXXVQNSA-N 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
- 239000000546 pharmaceutical excipient Substances 0.000 description 6
- WSJGMGPBDAOSKR-HNNXBMFYSA-N (2s)-3-cyclohexyl-2-(7-fluoro-3-oxo-1h-isoindol-2-yl)propanoic acid Chemical compound C([C@@H](C(=O)O)N1C(C2=C(C(=CC=C2)F)C1)=O)C1CCCCC1 WSJGMGPBDAOSKR-HNNXBMFYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 150000001204 N-oxides Chemical class 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- 238000007796 conventional method Methods 0.000 description 5
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 5
- 238000011534 incubation Methods 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 238000004007 reversed phase HPLC Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical compound NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 description 4
- JTYBTJVFXUKNKW-UHFFFAOYSA-N 2-(2,4,5-trifluorophenyl)acetonitrile Chemical compound FC1=CC(F)=C(CC#N)C=C1F JTYBTJVFXUKNKW-UHFFFAOYSA-N 0.000 description 4
- BBCQSMSCEJBIRD-UHFFFAOYSA-N 3-fluorophthalic acid Chemical compound OC(=O)C1=CC=CC(F)=C1C(O)=O BBCQSMSCEJBIRD-UHFFFAOYSA-N 0.000 description 4
- GAHFFZDPDRNMNC-UHFFFAOYSA-N 4-fluoro-2,3-dihydroisoindol-1-one Chemical compound FC1=CC=CC2=C1CNC2=O GAHFFZDPDRNMNC-UHFFFAOYSA-N 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- UAXMLIVNXZKEOV-UHFFFAOYSA-N [3-fluoro-2-(hydroxymethyl)phenyl]methanol Chemical compound OCC1=CC=CC(F)=C1CO UAXMLIVNXZKEOV-UHFFFAOYSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 125000006242 amine protecting group Chemical group 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 125000002619 bicyclic group Chemical group 0.000 description 4
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 238000009833 condensation Methods 0.000 description 4
- 230000005494 condensation Effects 0.000 description 4
- 230000004153 glucose metabolism Effects 0.000 description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- 229920005862 polyol Polymers 0.000 description 4
- 150000003077 polyols Chemical class 0.000 description 4
- 239000000651 prodrug Substances 0.000 description 4
- 229940002612 prodrug Drugs 0.000 description 4
- XFTQRUTUGRCSGO-UHFFFAOYSA-N pyrazin-2-amine Chemical compound NC1=CN=CC=N1 XFTQRUTUGRCSGO-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 150000003222 pyridines Chemical class 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 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 4
- LCUKXLCZLIIJLV-HNNXBMFYSA-N (2s)-2-(7-chloro-3-oxo-1h-isoindol-2-yl)-3-cyclohexylpropanoic acid Chemical compound C([C@@H](C(=O)O)N1C(C2=C(C(=CC=C2)Cl)C1)=O)C1CCCCC1 LCUKXLCZLIIJLV-HNNXBMFYSA-N 0.000 description 3
- HDJQIWAIDCEDEF-QRPNPIFTSA-N (2s)-2-amino-3-cyclohexylpropanoic acid;hydrate Chemical compound O.OC(=O)[C@@H](N)CC1CCCCC1 HDJQIWAIDCEDEF-QRPNPIFTSA-N 0.000 description 3
- MOTYSUWGCCIXCJ-INIZCTEOSA-N (2s)-3-cyclohexyl-2-(4-fluoro-3-oxo-1h-isoindol-2-yl)-n-(1,3-thiazol-2-yl)propanamide Chemical compound C([C@H](N1CC=2C=CC=C(C=2C1=O)F)C(=O)NC=1SC=CN=1)C1CCCCC1 MOTYSUWGCCIXCJ-INIZCTEOSA-N 0.000 description 3
- LHNQWIYWCFTZSJ-AWEZNQCLSA-N (2s)-3-cyclohexyl-2-(4-fluoro-3-oxo-1h-isoindol-2-yl)propanoic acid Chemical compound C([C@@H](C(=O)O)N1C(C2=C(F)C=CC=C2C1)=O)C1CCCCC1 LHNQWIYWCFTZSJ-AWEZNQCLSA-N 0.000 description 3
- CZPDANYBRUJHEO-HNNXBMFYSA-N (2s)-3-cyclohexyl-2-(5,6-dichloro-3-oxo-1h-isoindol-2-yl)propanoic acid Chemical compound C([C@@H](C(=O)O)N1C(C2=CC(Cl)=C(Cl)C=C2C1)=O)C1CCCCC1 CZPDANYBRUJHEO-HNNXBMFYSA-N 0.000 description 3
- GBNHOHZADLLVKN-KRWDZBQOSA-N (2s)-3-cyclohexyl-2-(7-fluoro-3-oxo-1h-isoindol-2-yl)-n-(1,3-thiazol-2-yl)propanamide Chemical compound C([C@H](N1C(=O)C=2C=CC=C(C=2C1)F)C(=O)NC=1SC=CN=1)C1CCCCC1 GBNHOHZADLLVKN-KRWDZBQOSA-N 0.000 description 3
- FDOQKGWUMUEJLX-UHFFFAOYSA-N 4,5-dichlorophthalic acid Chemical compound OC(=O)C1=CC(Cl)=C(Cl)C=C1C(O)=O FDOQKGWUMUEJLX-UHFFFAOYSA-N 0.000 description 3
- 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 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 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 3
- 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 3
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 3
- 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 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- NDQYVFKHPRRCSL-UHFFFAOYSA-N [3-chloro-2-(hydroxymethyl)phenyl]methanol Chemical compound OCC1=CC=CC(Cl)=C1CO NDQYVFKHPRRCSL-UHFFFAOYSA-N 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000003153 chemical reaction reagent 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
- 239000008298 dragée Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000002255 enzymatic effect Effects 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- 102000010705 glucose-6-phosphate dehydrogenase activity proteins Human genes 0.000 description 3
- 108040005050 glucose-6-phosphate dehydrogenase activity proteins Proteins 0.000 description 3
- 210000003494 hepatocyte Anatomy 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 235000019260 propionic acid Nutrition 0.000 description 3
- 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 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- GEKUFTBQNVFPHS-OAHLLOKOSA-N (2r)-3-cyclohexyl-2-(3-oxo-1h-isoindol-2-yl)propanoic acid Chemical compound C([C@H](C(=O)O)N1C(C2=CC=CC=C2C1)=O)C1CCCCC1 GEKUFTBQNVFPHS-OAHLLOKOSA-N 0.000 description 2
- VFFPWUGCWCCOLR-INIZCTEOSA-N (2s)-2-(7-chloro-3-oxo-1h-isoindol-2-yl)-n-(5-chloro-1,3-thiazol-2-yl)-3-cyclohexylpropanamide Chemical compound S1C(Cl)=CN=C1NC(=O)[C@@H](N1C(C2=C(C(=CC=C2)Cl)C1)=O)CC1CCCCC1 VFFPWUGCWCCOLR-INIZCTEOSA-N 0.000 description 2
- XVQGNUFYAJIZQR-SFHVURJKSA-N (2s)-3-cyclohexyl-2-(3-oxo-1h-isoindol-2-yl)-n-pyrazin-2-ylpropanamide Chemical compound O=C([C@H](CC1CCCCC1)N1C(C2=CC=CC=C2C1)=O)NC1=CN=CC=N1 XVQGNUFYAJIZQR-SFHVURJKSA-N 0.000 description 2
- OWKBKSGHGBDMNC-HNNXBMFYSA-N (2s)-3-cyclohexyl-2-(6-nitro-3-oxo-1h-isoindol-2-yl)propanoic acid Chemical compound C([C@@H](C(=O)O)N1C(C2=CC=C(C=C2C1)[N+]([O-])=O)=O)C1CCCCC1 OWKBKSGHGBDMNC-HNNXBMFYSA-N 0.000 description 2
- RXKUQKUECLOWDJ-KRWDZBQOSA-N (2s)-3-cyclohexyl-n-(1h-imidazol-2-yl)-2-(3-oxo-1h-isoindol-2-yl)propanamide Chemical compound O=C([C@H](CC1CCCCC1)N1C(C2=CC=CC=C2C1)=O)NC1=NC=CN1 RXKUQKUECLOWDJ-KRWDZBQOSA-N 0.000 description 2
- RLBRXNUSTWYTMA-FQEVSTJZSA-N (2s)-3-cyclohexyl-n-(5-methylpyridin-2-yl)-2-(3-oxo-1h-isoindol-2-yl)propanamide Chemical compound N1=CC(C)=CC=C1NC(=O)[C@@H](N1C(C2=CC=CC=C2C1)=O)CC1CCCCC1 RLBRXNUSTWYTMA-FQEVSTJZSA-N 0.000 description 2
- JRASWERIVQXADO-NRFANRHFSA-N (2s)-n-(1h-benzimidazol-2-yl)-3-cyclohexyl-2-(3-oxo-1h-isoindol-2-yl)propanamide Chemical compound C([C@@H](C(NC=1NC2=CC=CC=C2N=1)=O)N1C(C2=CC=CC=C2C1)=O)C1CCCCC1 JRASWERIVQXADO-NRFANRHFSA-N 0.000 description 2
- UYCVBXJBAQSWQH-INIZCTEOSA-N (2s)-n-(5-bromo-1,3-thiazol-2-yl)-3-cyclohexyl-2-(3-oxo-1h-isoindol-2-yl)propanamide Chemical compound S1C(Br)=CN=C1NC(=O)[C@@H](N1C(C2=CC=CC=C2C1)=O)CC1CCCCC1 UYCVBXJBAQSWQH-INIZCTEOSA-N 0.000 description 2
- GCMNJUJAKQGROZ-UHFFFAOYSA-N 1,2-Dihydroquinolin-2-imine Chemical compound C1=CC=CC2=NC(N)=CC=C21 GCMNJUJAKQGROZ-UHFFFAOYSA-N 0.000 description 2
- DEPDDPLQZYCHOH-UHFFFAOYSA-N 1h-imidazol-2-amine Chemical compound NC1=NC=CN1 DEPDDPLQZYCHOH-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
- PSYRORCNCYQOIA-UHFFFAOYSA-N 2-amino-3-cyclooctylpropanoic acid Chemical compound OC(=O)C(N)CC1CCCCCCC1 PSYRORCNCYQOIA-UHFFFAOYSA-N 0.000 description 2
- WLPDUJITFJCPFH-UHFFFAOYSA-N 2-cycloheptylethanol Chemical compound OCCC1CCCCCC1 WLPDUJITFJCPFH-UHFFFAOYSA-N 0.000 description 2
- BKFXSOCDAQACQM-UHFFFAOYSA-N 3-chlorophthalic acid Chemical compound OC(=O)C1=CC=CC(Cl)=C1C(O)=O BKFXSOCDAQACQM-UHFFFAOYSA-N 0.000 description 2
- GEKUFTBQNVFPHS-UHFFFAOYSA-N 3-cyclohexyl-2-(3-oxo-1h-isoindol-2-yl)propanoic acid Chemical compound C1C2=CC=CC=C2C(=O)N1C(C(=O)O)CC1CCCCC1 GEKUFTBQNVFPHS-UHFFFAOYSA-N 0.000 description 2
- 239000004342 Benzoyl peroxide Substances 0.000 description 2
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- VZFUCHSFHOYXIS-UHFFFAOYSA-N Cycloheptanecarboxylic acid Chemical compound OC(=O)C1CCCCCC1 VZFUCHSFHOYXIS-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- 101150109586 Gk gene Proteins 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 102000005548 Hexokinase Human genes 0.000 description 2
- 108700040460 Hexokinases Proteins 0.000 description 2
- 208000013016 Hypoglycemia Diseases 0.000 description 2
- 235000019759 Maize starch Nutrition 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- BVWREOCJVMLGTJ-UHFFFAOYSA-N [2-(hydroxymethyl)-4-nitrophenyl]methanol Chemical compound OCC1=CC=C([N+]([O-])=O)C=C1CO BVWREOCJVMLGTJ-UHFFFAOYSA-N 0.000 description 2
- WSCRUXVCUXHCOW-UHFFFAOYSA-N [4,5-dichloro-2-(hydroxymethyl)phenyl]methanol Chemical compound OCC1=CC(Cl)=C(Cl)C=C1CO WSCRUXVCUXHCOW-UHFFFAOYSA-N 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- 239000011260 aqueous acid Substances 0.000 description 2
- 125000005872 benzooxazolyl group Chemical group 0.000 description 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 2
- 235000019400 benzoyl peroxide Nutrition 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 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
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 150000002009 diols Chemical class 0.000 description 2
- 125000001033 ether group Chemical group 0.000 description 2
- 239000003925 fat Substances 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 230000014101 glucose homeostasis Effects 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000001727 in vivo Methods 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
- 239000000543 intermediate Substances 0.000 description 2
- REEPTAINTWFSIK-UHFFFAOYSA-N iodomethylcyclooctane Chemical compound ICC1CCCCCCC1 REEPTAINTWFSIK-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 210000004185 liver Anatomy 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
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- 150000003022 phthalic acids Chemical class 0.000 description 2
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- OYRRZWATULMEPF-UHFFFAOYSA-N pyrimidin-4-amine Chemical compound NC1=CC=NC=N1 OYRRZWATULMEPF-UHFFFAOYSA-N 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- IEIIYAAYMXWZHA-UHFFFAOYSA-N tert-butyl 2-(benzhydrylideneamino)-3-cyclooctylpropanoate Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)=NC(C(=O)OC(C)(C)C)CC1CCCCCCC1 IEIIYAAYMXWZHA-UHFFFAOYSA-N 0.000 description 2
- YSHDPXQDVKNPKA-UHFFFAOYSA-N tert-butyl 2-(benzhydrylideneamino)acetate Chemical compound C=1C=CC=CC=1C(=NCC(=O)OC(C)(C)C)C1=CC=CC=C1 YSHDPXQDVKNPKA-UHFFFAOYSA-N 0.000 description 2
- 150000003557 thiazoles Chemical class 0.000 description 2
- 239000001993 wax Substances 0.000 description 2
- ORQXBVXKBGUSBA-QMMMGPOBSA-N β-cyclohexyl-alanine Chemical compound OC(=O)[C@@H](N)CC1CCCCC1 ORQXBVXKBGUSBA-QMMMGPOBSA-N 0.000 description 2
- MQKCRBMWUJVVQX-KRWDZBQOSA-N (2S)-3-cyclohexyl-2-(4-methylsulfonyl-3-oxo-1H-isoindol-2-yl)-N-pyrimidin-2-ylpropanamide Chemical compound C1(CCCCC1)C[C@@H](C(=O)NC1=NC=CC=N1)N1C(C2=C(C=CC=C2C1)S(=O)(=O)C)=O MQKCRBMWUJVVQX-KRWDZBQOSA-N 0.000 description 1
- WPJDQCYEKASFFN-SFHVURJKSA-N (2S)-3-cyclohexyl-2-(7-methylsulfonyl-3-oxo-1H-isoindol-2-yl)-N-pyrimidin-2-ylpropanamide Chemical compound C1(CCCCC1)C[C@@H](C(=O)NC1=NC=CC=N1)N1C(C2=CC=CC(=C2C1)S(=O)(=O)C)=O WPJDQCYEKASFFN-SFHVURJKSA-N 0.000 description 1
- XHWIOENGQYROJH-INIZCTEOSA-N (2s)-2-(4-chloro-3-oxo-1h-isoindol-2-yl)-3-cyclohexyl-n-(1,3-thiazol-2-yl)propanamide Chemical compound C([C@H](N1CC=2C=CC=C(C=2C1=O)Cl)C(=O)NC=1SC=CN=1)C1CCCCC1 XHWIOENGQYROJH-INIZCTEOSA-N 0.000 description 1
- ADKARQQIMWDUGM-IBGZPJMESA-N (2s)-2-(7-chloro-3-oxo-1h-isoindol-2-yl)-3-cyclohexyl-n-pyridin-2-ylpropanamide Chemical compound C([C@H](N1C(=O)C=2C=CC=C(C=2C1)Cl)C(=O)NC=1N=CC=CC=1)C1CCCCC1 ADKARQQIMWDUGM-IBGZPJMESA-N 0.000 description 1
- HEANFYSBOROOGI-SFHVURJKSA-N (2s)-3-cyclohexyl-2-(4-fluoro-3-oxo-1h-isoindol-2-yl)-n-pyridin-2-ylpropanamide Chemical compound C([C@H](N1CC=2C=CC=C(C=2C1=O)F)C(=O)NC=1N=CC=CC=1)C1CCCCC1 HEANFYSBOROOGI-SFHVURJKSA-N 0.000 description 1
- NJZNFKXZYGYLHJ-INIZCTEOSA-N (2s)-3-cyclohexyl-2-(4-methylsulfonyl-3-oxo-1h-isoindol-2-yl)-n-(1,3-thiazol-2-yl)propanamide Chemical compound C([C@H](N1CC=2C=CC=C(C=2C1=O)S(=O)(=O)C)C(=O)NC=1SC=CN=1)C1CCCCC1 NJZNFKXZYGYLHJ-INIZCTEOSA-N 0.000 description 1
- KDUXDFOIUUGGRR-KRWDZBQOSA-N (2s)-3-cyclohexyl-2-(5-nitro-3-oxo-1h-isoindol-2-yl)-n-(1,3-thiazol-2-yl)propanamide Chemical compound C([C@H](N1CC2=CC=C(C=C2C1=O)[N+](=O)[O-])C(=O)NC=1SC=CN=1)C1CCCCC1 KDUXDFOIUUGGRR-KRWDZBQOSA-N 0.000 description 1
- PQWVLWHMNCYCSN-HNNXBMFYSA-N (2s)-3-cyclohexyl-2-(5-nitro-3-oxo-1h-isoindol-2-yl)propanoic acid Chemical compound C([C@@H](C(=O)O)N1C(C2=CC(=CC=C2C1)[N+]([O-])=O)=O)C1CCCCC1 PQWVLWHMNCYCSN-HNNXBMFYSA-N 0.000 description 1
- DQKKRPDGDNRFGW-KRWDZBQOSA-N (2s)-3-cyclohexyl-2-(6-nitro-3-oxo-1h-isoindol-2-yl)-n-(1,3-thiazol-2-yl)propanamide Chemical compound C([C@H](N1C(=O)C2=CC=C(C=C2C1)[N+](=O)[O-])C(=O)NC=1SC=CN=1)C1CCCCC1 DQKKRPDGDNRFGW-KRWDZBQOSA-N 0.000 description 1
- FHBWVXBMWRLART-IBGZPJMESA-N (2s)-3-cyclohexyl-2-(7-fluoro-3-oxo-1h-isoindol-2-yl)-n-pyridin-2-ylpropanamide Chemical compound C([C@H](N1C(=O)C=2C=CC=C(C=2C1)F)C(=O)NC=1N=CC=CC=1)C1CCCCC1 FHBWVXBMWRLART-IBGZPJMESA-N 0.000 description 1
- BVSOQGZWTORSTO-HNNXBMFYSA-N (2s)-3-cyclohexyl-2-(7-methylsulfanyl-3-oxo-1h-isoindol-2-yl)propanoic acid Chemical compound C([C@H](N1C(=O)C=2C=CC=C(C=2C1)SC)C(O)=O)C1CCCCC1 BVSOQGZWTORSTO-HNNXBMFYSA-N 0.000 description 1
- AMYSZDQNPNHAGO-KRWDZBQOSA-N (2s)-3-cyclohexyl-2-(7-methylsulfonyl-3-oxo-1h-isoindol-2-yl)-n-(1,3-thiazol-2-yl)propanamide Chemical compound C([C@H](N1C(=O)C=2C=CC=C(C=2C1)S(=O)(=O)C)C(=O)NC=1SC=CN=1)C1CCCCC1 AMYSZDQNPNHAGO-KRWDZBQOSA-N 0.000 description 1
- PFDSEUJLJPKGSE-HNNXBMFYSA-N (2s)-3-cyclohexyl-2-(7-methylsulfonyl-3-oxo-1h-isoindol-2-yl)propanoic acid Chemical compound C([C@H](N1C(=O)C=2C=CC=C(C=2C1)S(=O)(=O)C)C(O)=O)C1CCCCC1 PFDSEUJLJPKGSE-HNNXBMFYSA-N 0.000 description 1
- NUKAOIIENHSHHP-INIZCTEOSA-N (2s)-n-(5-chloro-1,3-thiazol-2-yl)-3-cyclohexyl-2-(3-oxo-1h-isoindol-2-yl)propanamide Chemical compound S1C(Cl)=CN=C1NC(=O)[C@@H](N1C(C2=CC=CC=C2C1)=O)CC1CCCCC1 NUKAOIIENHSHHP-INIZCTEOSA-N 0.000 description 1
- SLCOTHPFAXVLDC-INIZCTEOSA-N (2s)-n-(5-chloro-1,3-thiazol-2-yl)-3-cyclohexyl-2-(5,6-dichloro-3-oxo-1h-isoindol-2-yl)propanamide Chemical compound S1C(Cl)=CN=C1NC(=O)[C@@H](N1C(C2=CC(Cl)=C(Cl)C=C2C1)=O)CC1CCCCC1 SLCOTHPFAXVLDC-INIZCTEOSA-N 0.000 description 1
- 125000006763 (C3-C9) cycloalkyl group Chemical group 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- JPBLHOJFMBOCAF-UHFFFAOYSA-N 1,3-benzoxazol-2-amine Chemical compound C1=CC=C2OC(N)=NC2=C1 JPBLHOJFMBOCAF-UHFFFAOYSA-N 0.000 description 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- KTPMVZCGIJJWCD-UHFFFAOYSA-N 1-hydroxypyridin-2-imine Chemical compound ON1C=CC=CC1=N KTPMVZCGIJJWCD-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- NOGFHTGYPKWWRX-UHFFFAOYSA-N 2,2,6,6-tetramethyloxan-4-one Chemical compound CC1(C)CC(=O)CC(C)(C)O1 NOGFHTGYPKWWRX-UHFFFAOYSA-N 0.000 description 1
- UWCWUCKPEYNDNV-LBPRGKRZSA-N 2,6-dimethyl-n-[[(2s)-pyrrolidin-2-yl]methyl]aniline Chemical compound CC1=CC=CC(C)=C1NC[C@H]1NCCC1 UWCWUCKPEYNDNV-LBPRGKRZSA-N 0.000 description 1
- OGNHGQOTYHQMQC-UHFFFAOYSA-N 2-(1,3-thiazol-2-yl)propanamide Chemical compound NC(=O)C(C)C1=NC=CS1 OGNHGQOTYHQMQC-UHFFFAOYSA-N 0.000 description 1
- UUNGVOGAQGEPOE-UHFFFAOYSA-N 2-(3-oxo-1h-isoindol-2-yl)-n-(1,3-thiazol-2-yl)propanamide Chemical compound C1C2=CC=CC=C2C(=O)N1C(C)C(=O)NC1=NC=CS1 UUNGVOGAQGEPOE-UHFFFAOYSA-N 0.000 description 1
- JYNKCKHZKNDMEE-UHFFFAOYSA-N 2-(4-chloro-3-oxo-1H-isoindol-2-yl)propanoic acid Chemical compound ClC=1C=CC=C2CN(C(C=12)=O)C(C(=O)O)C JYNKCKHZKNDMEE-UHFFFAOYSA-N 0.000 description 1
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 1
- HUHXLHLWASNVDB-UHFFFAOYSA-N 2-(oxan-2-yloxy)oxane Chemical class O1CCCCC1OC1OCCCC1 HUHXLHLWASNVDB-UHFFFAOYSA-N 0.000 description 1
- GHCFWKFREBNSPC-UHFFFAOYSA-N 2-Amino-4-methylpyrimidine Chemical compound CC1=CC=NC(N)=N1 GHCFWKFREBNSPC-UHFFFAOYSA-N 0.000 description 1
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
- JWYUFVNJZUSCSM-UHFFFAOYSA-N 2-aminobenzimidazole Chemical compound C1=CC=C2NC(N)=NC2=C1 JWYUFVNJZUSCSM-UHFFFAOYSA-N 0.000 description 1
- UHGULLIUJBCTEF-UHFFFAOYSA-N 2-aminobenzothiazole Chemical compound C1=CC=C2SC(N)=NC2=C1 UHGULLIUJBCTEF-UHFFFAOYSA-N 0.000 description 1
- KDYAKYRBGLKMAK-UHFFFAOYSA-N 2-azaniumyl-3-cyclopentylpropanoate Chemical compound OC(=O)C(N)CC1CCCC1 KDYAKYRBGLKMAK-UHFFFAOYSA-N 0.000 description 1
- JEXQWCBPEWHFKC-UHFFFAOYSA-N 2-cyclopentylethanol Chemical compound OCCC1CCCC1 JEXQWCBPEWHFKC-UHFFFAOYSA-N 0.000 description 1
- ZCMILLAOXOEWPJ-UHFFFAOYSA-N 2-pyridin-2-ylpropanamide Chemical compound NC(=O)C(C)C1=CC=CC=N1 ZCMILLAOXOEWPJ-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- PWPUNWJDAFANEV-UHFFFAOYSA-N 3-cyclopentyl-2-(3-oxo-1h-isoindol-2-yl)-n-(1,3-thiazol-2-yl)propanamide Chemical compound C1CCCC1CC(N1C(C2=CC=CC=C2C1)=O)C(=O)NC1=NC=CS1 PWPUNWJDAFANEV-UHFFFAOYSA-N 0.000 description 1
- YXOAUUWLNQFGOQ-UHFFFAOYSA-N 3-cyclopentyl-2-(3-oxo-1h-isoindol-2-yl)propanoic acid Chemical compound C1C2=CC=CC=C2C(=O)N1C(C(=O)O)CC1CCCC1 YXOAUUWLNQFGOQ-UHFFFAOYSA-N 0.000 description 1
- UCZAYZNTAWBJRF-UHFFFAOYSA-N 4-chloro-2,3-dihydroisoindol-1-one Chemical compound ClC1=CC=CC2=C1CNC2=O UCZAYZNTAWBJRF-UHFFFAOYSA-N 0.000 description 1
- ORLGLBZRQYOWNA-UHFFFAOYSA-N 4-methylpyridin-2-amine Chemical compound CC1=CC=NC(N)=C1 ORLGLBZRQYOWNA-UHFFFAOYSA-N 0.000 description 1
- SLBQXWXKPNIVSQ-UHFFFAOYSA-N 4-nitrophthalic acid Chemical compound OC(=O)C1=CC=C([N+]([O-])=O)C=C1C(O)=O SLBQXWXKPNIVSQ-UHFFFAOYSA-N 0.000 description 1
- XFDCNXIWKCIBAE-UHFFFAOYSA-N 5-bromo-1,3-thiazol-2-amine;hydrochloride Chemical compound Cl.NC1=NC=C(Br)S1 XFDCNXIWKCIBAE-UHFFFAOYSA-N 0.000 description 1
- WGOLHUGPTDEKCF-UHFFFAOYSA-N 5-bromopyridin-2-amine Chemical compound NC1=CC=C(Br)C=N1 WGOLHUGPTDEKCF-UHFFFAOYSA-N 0.000 description 1
- NWOLGGTYWDKMCH-UHFFFAOYSA-N 5-chloro-1,3-thiazole hydrochloride Chemical compound Cl.Clc1cncs1 NWOLGGTYWDKMCH-UHFFFAOYSA-N 0.000 description 1
- WJRKNLONLOMALV-UHFFFAOYSA-N 5-chloropyridine Chemical compound ClC1=C=NC=C[CH]1 WJRKNLONLOMALV-UHFFFAOYSA-N 0.000 description 1
- CMBSSVKZOPZBKW-UHFFFAOYSA-N 5-methylpyridin-2-amine Chemical compound CC1=CC=C(N)N=C1 CMBSSVKZOPZBKW-UHFFFAOYSA-N 0.000 description 1
- NVKJOXRVEKMMHS-UHFFFAOYSA-N 5-nitro-1,2,4-triazol-3-one Chemical compound [O-][N+](=O)C1=NC(=O)N=N1 NVKJOXRVEKMMHS-UHFFFAOYSA-N 0.000 description 1
- CZXUANYPXDFFOG-UHFFFAOYSA-N 5-nitro-2,3-dihydroisoindol-1-one Chemical compound [O-][N+](=O)C1=CC=C2C(=O)NCC2=C1 CZXUANYPXDFFOG-UHFFFAOYSA-N 0.000 description 1
- IJOJIVNDFQSGAB-SQOUGZDYSA-N 6-O-phosphono-D-glucono-1,5-lactone Chemical compound O[C@H]1[C@H](O)[C@@H](COP(O)(O)=O)OC(=O)[C@@H]1O IJOJIVNDFQSGAB-SQOUGZDYSA-N 0.000 description 1
- 102100031126 6-phosphogluconolactonase Human genes 0.000 description 1
- 108010029731 6-phosphogluconolactonase Proteins 0.000 description 1
- ZZTUZMIZZLVYHG-UHFFFAOYSA-N 7-fluoro-2,3-dihydroisoindol-1-one Chemical compound FC1=CC=CC2=C1C(=O)NC2 ZZTUZMIZZLVYHG-UHFFFAOYSA-N 0.000 description 1
- 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 1
- ZZOKVYOCRSMTSS-UHFFFAOYSA-N 9h-fluoren-9-ylmethyl carbamate Chemical compound C1=CC=C2C(COC(=O)N)C3=CC=CC=C3C2=C1 ZZOKVYOCRSMTSS-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 210000002237 B-cell of pancreatic islet Anatomy 0.000 description 1
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 1
- 229910014265 BrCl Inorganic materials 0.000 description 1
- IRAAHDSHPDYZFE-UHFFFAOYSA-N C1CCC(CC1)CC(C2=NC=C(S2)Cl)(C(=O)N)N3CC4=C(C3=O)C(=CC=C4)F Chemical compound C1CCC(CC1)CC(C2=NC=C(S2)Cl)(C(=O)N)N3CC4=C(C3=O)C(=CC=C4)F IRAAHDSHPDYZFE-UHFFFAOYSA-N 0.000 description 1
- ZGERBPFZVJZNOD-MLCCFXAWSA-N C1CCC(CC1)C[C@@H](C(=O)O)N2C(C3=CC=CC=C3C2=O)Cl Chemical compound C1CCC(CC1)C[C@@H](C(=O)O)N2C(C3=CC=CC=C3C2=O)Cl ZGERBPFZVJZNOD-MLCCFXAWSA-N 0.000 description 1
- MSZJPWODXUXUGZ-UHFFFAOYSA-N C1CCCC(CC1)CC(C(=O)O)N=C(C2=CC=CC=C2)C3=CC=CC=C3 Chemical compound C1CCCC(CC1)CC(C(=O)O)N=C(C2=CC=CC=C2)C3=CC=CC=C3 MSZJPWODXUXUGZ-UHFFFAOYSA-N 0.000 description 1
- VIPWGMMDZOTSGY-UHFFFAOYSA-N C1CCCCC1CC(N1C(C2=CC=CC=C2C1)=O)C(=O)NC1=CC=CC=N1 Chemical compound C1CCCCC1CC(N1C(C2=CC=CC=C2C1)=O)C(=O)NC1=CC=CC=N1 VIPWGMMDZOTSGY-UHFFFAOYSA-N 0.000 description 1
- 238000011746 C57BL/6J (JAX™ mouse strain) Methods 0.000 description 1
- MLNIXGSLKCSAFU-UHFFFAOYSA-N CC(C(=O)N)N1C=C2C=CC=CC2=C1 Chemical compound CC(C(=O)N)N1C=C2C=CC=CC2=C1 MLNIXGSLKCSAFU-UHFFFAOYSA-N 0.000 description 1
- YQPDPHCNTQPHDN-UHFFFAOYSA-N CC(C(=O)NC1=NC=CN=C1)N2CC3=C(C2=O)C=CC=C3Cl Chemical compound CC(C(=O)NC1=NC=CN=C1)N2CC3=C(C2=O)C=CC=C3Cl YQPDPHCNTQPHDN-UHFFFAOYSA-N 0.000 description 1
- 235000001258 Cinchona calisaya Nutrition 0.000 description 1
- AXRGXOGIDBVNGP-UHFFFAOYSA-N ClC1=CN=C(S1)C(C(=O)N)(CC1CCCCC1)N1C(C2=CC(=C(C=C2C1)Cl)Cl)=O Chemical compound ClC1=CN=C(S1)C(C(=O)N)(CC1CCCCC1)N1C(C2=CC(=C(C=C2C1)Cl)Cl)=O AXRGXOGIDBVNGP-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
- 241000196324 Embryophyta Species 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 206010064571 Gene mutation Diseases 0.000 description 1
- 108010018962 Glucosephosphate Dehydrogenase Proteins 0.000 description 1
- 102100023903 Glycerol kinase Human genes 0.000 description 1
- 229920002527 Glycogen Polymers 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 241000192130 Leuconostoc mesenteroides Species 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- AQBIOZLJIVVLSH-UHFFFAOYSA-N N-(3-oxo-1H-isoindol-2-yl)propanamide Chemical compound CCC(=O)NN1Cc2ccccc2C1=O AQBIOZLJIVVLSH-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-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
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Natural products C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 1
- 229920002684 Sepharose Polymers 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 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
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- XMUZQOKACOLCSS-UHFFFAOYSA-N [2-(hydroxymethyl)phenyl]methanol Chemical compound OCC1=CC=CC=C1CO XMUZQOKACOLCSS-UHFFFAOYSA-N 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229950011175 aminopicoline Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- PUJDIJCNWFYVJX-UHFFFAOYSA-N benzyl carbamate Chemical compound NC(=O)OCC1=CC=CC=C1 PUJDIJCNWFYVJX-UHFFFAOYSA-N 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
- CODNYICXDISAEA-UHFFFAOYSA-N bromine monochloride Chemical compound BrCl CODNYICXDISAEA-UHFFFAOYSA-N 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical class OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 description 1
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- ZHPBLHYKDKSZCQ-UHFFFAOYSA-N cyclooctylmethanol Chemical compound OCC1CCCCCCC1 ZHPBLHYKDKSZCQ-UHFFFAOYSA-N 0.000 description 1
- CHGPELMANYOUNH-UHFFFAOYSA-N dimethyl 3-fluorobenzene-1,2-dicarboxylate Chemical compound COC(=O)C1=CC=CC(F)=C1C(=O)OC CHGPELMANYOUNH-UHFFFAOYSA-N 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- 238000006073 displacement reaction 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
- 239000002552 dosage form Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 150000003948 formamides Chemical group 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229940124828 glucokinase activator Drugs 0.000 description 1
- 230000009229 glucose formation Effects 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229940096919 glycogen Drugs 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 125000006343 heptafluoro propyl group Chemical group 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UQEAIHBTYFGYIE-UHFFFAOYSA-N hexamethyldisiloxane Chemical compound C[Si](C)(C)O[Si](C)(C)C UQEAIHBTYFGYIE-UHFFFAOYSA-N 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 238000012750 in vivo screening Methods 0.000 description 1
- 239000008011 inorganic excipient Substances 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 238000011068 loading method Methods 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
- 238000004519 manufacturing process Methods 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-M methanethiolate Chemical compound [S-]C LSDPWZHWYPCBBB-UHFFFAOYSA-M 0.000 description 1
- WCYAALZQFZMMOM-UHFFFAOYSA-N methanol;sulfuric acid Chemical compound OC.OS(O)(=O)=O WCYAALZQFZMMOM-UHFFFAOYSA-N 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 229940050176 methyl chloride Drugs 0.000 description 1
- 150000002762 monocarboxylic acid derivatives Chemical class 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- JKHHPJPIEXQNBA-UHFFFAOYSA-N n-(1,3-benzothiazol-2-yl)-3-cyclohexyl-2-(3-oxo-1h-isoindol-2-yl)propanamide Chemical compound N=1C2=CC=CC=C2SC=1NC(=O)C(N1C(C2=CC=CC=C2C1)=O)CC1CCCCC1 JKHHPJPIEXQNBA-UHFFFAOYSA-N 0.000 description 1
- QJCZYKAVUAOAOA-UHFFFAOYSA-N n-(5-bromo-1,3-thiazol-2-yl)-3-cyclohexyl-2-(5,6-dichloro-3-oxo-1h-isoindol-2-yl)propanamide Chemical compound O=C1C=2C=C(Cl)C(Cl)=CC=2CN1C(C(=O)NC=1SC(Br)=CN=1)CC1CCCCC1 QJCZYKAVUAOAOA-UHFFFAOYSA-N 0.000 description 1
- DWKULHYELSMWDJ-UHFFFAOYSA-N n-[3-[1-[(2-chloro-6-fluorophenyl)methyl]benzimidazol-2-yl]propyl]-2-methoxyacetamide Chemical compound COCC(=O)NCCCC1=NC2=CC=CC=C2N1CC1=C(F)C=CC=C1Cl DWKULHYELSMWDJ-UHFFFAOYSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- UCWQHVABVFGEJB-UHFFFAOYSA-N n-pyrazin-2-ylpropanamide Chemical compound CCC(=O)NC1=CN=CC=N1 UCWQHVABVFGEJB-UHFFFAOYSA-N 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
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000006501 nitrophenyl group Chemical group 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000004305 normal phase HPLC Methods 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 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
- 239000008012 organic excipient Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 125000005010 perfluoroalkyl group Chemical group 0.000 description 1
- ZWLUXSQADUDCSB-UHFFFAOYSA-N phthalaldehyde Chemical compound O=CC1=CC=CC=C1C=O ZWLUXSQADUDCSB-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003216 pyrazines Chemical class 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000029964 regulation of glucose metabolic process Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- RMBAVIFYHOYIFM-UHFFFAOYSA-M sodium methanethiolate Chemical compound [Na+].[S-]C RMBAVIFYHOYIFM-UHFFFAOYSA-M 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 238000000638 solvent extraction Methods 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
- 239000007921 spray Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229940014800 succinic anhydride Drugs 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- WAPJVSYAZYVYAB-UHFFFAOYSA-N tert-butyl 2-(benzhydrylideneamino)-3-cycloheptylpropanoate Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)=NC(C(=O)OC(C)(C)C)CC1CCCCCC1 WAPJVSYAZYVYAB-UHFFFAOYSA-N 0.000 description 1
- XBXCNNQPRYLIDE-UHFFFAOYSA-N tert-butylcarbamic acid Chemical compound CC(C)(C)NC(O)=O XBXCNNQPRYLIDE-UHFFFAOYSA-N 0.000 description 1
- 125000004149 thio group Chemical group *S* 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Diabetes (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Endocrinology (AREA)
- Obesity (AREA)
- Emergency Medicine (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Indole Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Breeding Of Plants And Reproduction By Means Of Culturing (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US25527300P | 2000-12-13 | 2000-12-13 | |
| US31871501P | 2001-09-13 | 2001-09-13 | |
| PCT/EP2001/014404 WO2002048106A2 (en) | 2000-12-13 | 2001-12-07 | Isoindolin-1-one glucokinase activators |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| SK8732003A3 true SK8732003A3 (en) | 2004-04-06 |
Family
ID=26944583
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SK873-2003A SK8732003A3 (en) | 2000-12-13 | 2001-12-07 | Isoindolin-1-one glucokinase activators |
Country Status (36)
| Country | Link |
|---|---|
| US (1) | US6482951B2 (no) |
| EP (1) | EP1349856B1 (no) |
| JP (1) | JP4021766B2 (no) |
| KR (1) | KR100520651B1 (no) |
| CN (1) | CN1247574C (no) |
| AT (1) | ATE297922T1 (no) |
| AU (2) | AU2002238415B2 (no) |
| BG (1) | BG107903A (no) |
| BR (1) | BR0116169A (no) |
| CA (1) | CA2430579C (no) |
| CY (1) | CY1105587T1 (no) |
| CZ (1) | CZ20031882A3 (no) |
| DE (1) | DE60111570T2 (no) |
| DK (1) | DK1349856T3 (no) |
| EG (1) | EG24358A (no) |
| ES (1) | ES2243578T3 (no) |
| HK (1) | HK1063314A1 (no) |
| HR (1) | HRP20030450B1 (no) |
| HU (1) | HUP0400587A3 (no) |
| IL (2) | IL156264A0 (no) |
| MA (1) | MA26973A1 (no) |
| MX (1) | MXPA03005170A (no) |
| MY (1) | MY136741A (no) |
| NO (1) | NO325810B1 (no) |
| NZ (1) | NZ526236A (no) |
| PA (1) | PA8534601A1 (no) |
| PE (1) | PE20020593A1 (no) |
| PL (1) | PL366006A1 (no) |
| PT (1) | PT1349856E (no) |
| RS (1) | RS50933B (no) |
| RU (1) | RU2249590C2 (no) |
| SI (1) | SI1349856T1 (no) |
| SK (1) | SK8732003A3 (no) |
| TW (1) | TWI294876B (no) |
| UY (1) | UY27069A1 (no) |
| WO (1) | WO2002048106A2 (no) |
Families Citing this family (46)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE0102299D0 (sv) | 2001-06-26 | 2001-06-26 | Astrazeneca Ab | Compounds |
| SE0102764D0 (sv) | 2001-08-17 | 2001-08-17 | Astrazeneca Ab | Compounds |
| CN100348596C (zh) | 2002-10-03 | 2007-11-14 | 霍夫曼-拉罗奇有限公司 | 作为葡糖激酶(gk)激活剂的吲哚－3－甲酰胺 |
| CA2498089A1 (en) | 2002-10-03 | 2004-06-17 | Novartis Ag | Substituted (thiazol-2-yl) -amide or sulfonamide as glycokinase activators useful in the treatment of type 2 diabetes |
| GB0226931D0 (en) | 2002-11-19 | 2002-12-24 | Astrazeneca Ab | Chemical compounds |
| WO2004063194A1 (en) * | 2003-01-06 | 2004-07-29 | Eli Lilly And Company | Heteroaryl compounds |
| WO2004072066A1 (en) * | 2003-02-11 | 2004-08-26 | Prosidion Limited | Tri(cyclo) substituted amide glucokinase activator compounds |
| PL378117A1 (pl) * | 2003-02-11 | 2006-03-06 | Prosidion Limited | Tricyklopodstawione związki amidowe |
| US7320992B2 (en) * | 2003-08-25 | 2008-01-22 | Amgen Inc. | Substituted 2,3-dihydro-1h-isoindol-1-one derivatives and methods of use |
| KR20070006816A (ko) * | 2004-04-02 | 2007-01-11 | 노파르티스 아게 | 티아졸로피리딘 유도체, 이를 함유하는 제약 조성물 및글루코키나제 매개형 증상의 치료 방법 |
| PT1735322E (pt) | 2004-04-02 | 2012-01-12 | Novartis Ag | Derivados de sulfonamido-tiazolopiridina como activadores de glucoquinase úteis para o tratamento de diabetes de tipo 2 |
| KR20080040046A (ko) * | 2005-08-31 | 2008-05-07 | 아스텔라스세이야쿠 가부시키가이샤 | 티아졸 유도체 |
| JP2007063225A (ja) * | 2005-09-01 | 2007-03-15 | Takeda Chem Ind Ltd | イミダゾピリジン化合物 |
| CA2624102A1 (en) | 2005-09-29 | 2007-04-12 | Sanofi-Aventis | Phenyl- and pyridinyl- 1, 2 , 4 - oxadiazolone derivatives, processes for their preparation and their use as pharmaceuticals |
| GT200600428A (es) * | 2005-09-30 | 2007-05-21 | Compuestos organicos | |
| GT200600429A (es) * | 2005-09-30 | 2007-04-30 | Compuestos organicos | |
| JP2009513711A (ja) * | 2005-11-01 | 2009-04-02 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | グルコキナーゼのアロステリックモジュレーターとしての置換ピロロン |
| US8796313B2 (en) | 2005-11-01 | 2014-08-05 | Janssen Pharmaceutica N.V. | Substituted dihydroisoindolones as allosteric modulators of glucokinase |
| CA2628259A1 (en) * | 2005-11-01 | 2007-05-10 | Janssen Pharmaceutica N.V. | Dihydroisoindolones as allosteric modulators of glucokinase |
| CN101321747A (zh) * | 2005-11-01 | 2008-12-10 | 詹森药业有限公司 | 作为葡萄糖激酶变构调节剂的取代的环烷基吡咯酮类 |
| JP2009514835A (ja) * | 2005-11-03 | 2009-04-09 | プロシディオン・リミテッド | トリシクロ置換型アミド |
| JP2009515997A (ja) * | 2005-11-18 | 2009-04-16 | タケダ サン ディエゴ インコーポレイテッド | グルコキナーゼ活性剤 |
| EP2001875A2 (en) * | 2006-03-08 | 2008-12-17 | Takeda San Diego, Inc. | Glucokinase activators |
| PE20110235A1 (es) | 2006-05-04 | 2011-04-14 | Boehringer Ingelheim Int | Combinaciones farmaceuticas que comprenden linagliptina y metmorfina |
| JP5386350B2 (ja) | 2006-05-31 | 2014-01-15 | タケダ カリフォルニア インコーポレイテッド | グルコキナーゼ活性剤としての、インダゾールおよびイソインドール誘導体 |
| WO2008074694A1 (en) * | 2006-12-20 | 2008-06-26 | F. Hoffmann-La Roche Ag | Crystallization of glucokinase activators |
| JP5419706B2 (ja) * | 2006-12-20 | 2014-02-19 | タケダ カリフォルニア インコーポレイテッド | グルコキナーゼアクチベーター |
| TW200831081A (en) * | 2006-12-25 | 2008-08-01 | Kyorin Seiyaku Kk | Glucokinase activator |
| TW200902489A (en) * | 2007-03-07 | 2009-01-16 | Kyorin Seiyaku Kk | Glucokinase-activating substance |
| US8173645B2 (en) * | 2007-03-21 | 2012-05-08 | Takeda San Diego, Inc. | Glucokinase activators |
| CL2009000004A1 (es) * | 2008-01-15 | 2010-02-19 | Lilly Co Eli | Forma cristalina de r-2-(4-ciclopropansulfonil-fenil)-n-pirazin-2-il-3-(tetrahidropiran-4-il)-propionamida; composicion farmaceutica que comprende a dicha forma cristalina; y uso para el tratamiento de diabetes o hiperglicemia. |
| KR20100110367A (ko) * | 2008-01-24 | 2010-10-12 | 메르크 파텐트 게엠베하 | 당뇨병 치료를 위한 베타-아미노산 유도체들 |
| KR101608259B1 (ko) | 2008-04-28 | 2016-04-01 | 교린 세이야꾸 가부시키 가이샤 | 시클로펜틸아크릴산아미드 유도체 |
| UY31830A (es) | 2008-05-16 | 2010-01-05 | Takeda Pharmaceutical | Activadores de glucoquinasa |
| PE20110303A1 (es) * | 2008-09-11 | 2011-05-21 | Pfizer | Derivados de heteroaril acetamidas como activadores de glucoquinasa |
| WO2011123572A1 (en) | 2010-03-31 | 2011-10-06 | The Scripps Research Institute | Reprogramming cells |
| US8178689B2 (en) * | 2010-06-17 | 2012-05-15 | Hoffman-La Roche Inc. | Tricyclic compounds |
| US20130156720A1 (en) | 2010-08-27 | 2013-06-20 | Ironwood Pharmaceuticals, Inc. | Compositions and methods for treating or preventing metabolic syndrome and related diseases and disorders |
| US9616097B2 (en) | 2010-09-15 | 2017-04-11 | Synergy Pharmaceuticals, Inc. | Formulations of guanylate cyclase C agonists and methods of use |
| EA201391254A1 (ru) | 2011-03-01 | 2014-02-28 | Синерджи Фармасьютикалз Инк. | Способ получения агонистов гуанилатциклазы c |
| US8470866B2 (en) * | 2011-05-03 | 2013-06-25 | Hoffmann-La Roche Inc. | Isoindolinone derivatives |
| PL3004076T3 (pl) * | 2013-05-27 | 2020-04-30 | F.Hoffmann-La Roche Ag | Nowe związki 3,4-dihydro-2h-izochinolin-1-onowe i 2,3-dihydroizoindol-1-onowe |
| PT3004138T (pt) | 2013-06-05 | 2024-06-18 | Bausch Health Ireland Ltd | Agonistas ultrapuros de guanilato ciclase c, método de produção e utilização dos mesmos |
| CA2959208C (en) | 2014-08-29 | 2023-09-19 | Tes Pharma S.R.L. | Pyrimidine derivatives and their use as inhibitors of alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase |
| EP3526199B1 (en) | 2016-10-14 | 2022-04-13 | Tes Pharma S.r.l. | Inhibitors of alpha-amino-beta-carboxymuconic acid semialdehyde decarboxylase |
| CA3119509A1 (en) | 2018-11-20 | 2020-05-28 | Tes Pharma S.R.L | Inhibitors of alpha-amino-beta-carboxymuconic acid semialdehyde decarboxxylase |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2687147A1 (fr) * | 1992-02-11 | 1993-08-13 | Union Pharma Scient Appl | Nouveaux derives d'alpha-amino n-pyridyl benzene propanamide, leurs procedes de preparation, compositions pharmaceutiques les contenant. |
| EP1169312B1 (en) | 1999-03-29 | 2004-10-06 | F. Hoffmann-La Roche Ag | Glucokinase activators |
| EP1280801B1 (en) | 2000-05-03 | 2005-09-07 | F. Hoffmann-La Roche Ag | Hydantoin-containing glucokinase activators |
| DK1282611T3 (da) | 2000-05-08 | 2005-02-14 | Hoffmann La Roche | Substituerede phenylacetatamider og anvendelse deraf som glucokinaseaktivatorer |
-
2001
- 2001-12-06 US US10/010,978 patent/US6482951B2/en not_active Expired - Fee Related
- 2001-12-07 EP EP01986857A patent/EP1349856B1/en not_active Expired - Lifetime
- 2001-12-07 CN CNB018206107A patent/CN1247574C/zh not_active Expired - Fee Related
- 2001-12-07 WO PCT/EP2001/014404 patent/WO2002048106A2/en active IP Right Grant
- 2001-12-07 RU RU2003120512/04A patent/RU2249590C2/ru not_active IP Right Cessation
- 2001-12-07 DE DE60111570T patent/DE60111570T2/de not_active Expired - Lifetime
- 2001-12-07 CA CA2430579A patent/CA2430579C/en not_active Expired - Fee Related
- 2001-12-07 JP JP2002549637A patent/JP4021766B2/ja not_active Expired - Fee Related
- 2001-12-07 SK SK873-2003A patent/SK8732003A3/sk unknown
- 2001-12-07 AT AT01986857T patent/ATE297922T1/de active
- 2001-12-07 RS YUP-477/03A patent/RS50933B/sr unknown
- 2001-12-07 AU AU2002238415A patent/AU2002238415B2/en not_active Ceased
- 2001-12-07 SI SI200130381T patent/SI1349856T1/xx unknown
- 2001-12-07 ES ES01986857T patent/ES2243578T3/es not_active Expired - Lifetime
- 2001-12-07 MX MXPA03005170A patent/MXPA03005170A/es active IP Right Grant
- 2001-12-07 NZ NZ526236A patent/NZ526236A/xx unknown
- 2001-12-07 CZ CZ20031882A patent/CZ20031882A3/cs unknown
- 2001-12-07 KR KR10-2003-7007869A patent/KR100520651B1/ko not_active IP Right Cessation
- 2001-12-07 BR BR0116169-5A patent/BR0116169A/pt not_active Application Discontinuation
- 2001-12-07 AU AU3841502A patent/AU3841502A/xx active Pending
- 2001-12-07 PL PL01366006A patent/PL366006A1/xx unknown
- 2001-12-07 DK DK01986857T patent/DK1349856T3/da active
- 2001-12-07 IL IL15626401A patent/IL156264A0/xx unknown
- 2001-12-07 PT PT01986857T patent/PT1349856E/pt unknown
- 2001-12-07 HU HU0400587A patent/HUP0400587A3/hu unknown
- 2001-12-10 PA PA20018534601A patent/PA8534601A1/es unknown
- 2001-12-10 TW TW090130510A patent/TWI294876B/zh not_active IP Right Cessation
- 2001-12-10 EG EG20011316A patent/EG24358A/xx active
- 2001-12-11 MY MYPI20015613A patent/MY136741A/en unknown
- 2001-12-11 PE PE2001001234A patent/PE20020593A1/es not_active Application Discontinuation
- 2001-12-12 UY UY27069A patent/UY27069A1/es not_active Application Discontinuation
-
2003
- 2003-06-02 IL IL156264A patent/IL156264A/en not_active IP Right Cessation
- 2003-06-04 HR HR20030450A patent/HRP20030450B1/xx not_active IP Right Cessation
- 2003-06-12 MA MA27197A patent/MA26973A1/fr unknown
- 2003-06-12 NO NO20032674A patent/NO325810B1/no not_active IP Right Cessation
- 2003-06-13 BG BG107903A patent/BG107903A/bg unknown
-
2004
- 2004-08-11 HK HK04106031A patent/HK1063314A1/xx not_active IP Right Cessation
-
2005
- 2005-09-15 CY CY20051101133T patent/CY1105587T1/el unknown
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| SK8732003A3 (en) | Isoindolin-1-one glucokinase activators | |
| AU2002238415A1 (en) | Isoindolin-1-one glucokinase activators | |
| EP1549638B1 (en) | Indole-3-carboxamides as glucokinase (gk) activators | |
| JP3971189B2 (ja) | ｐ−アミノ置換フェニルアミドグルコキナーゼ活性化物質 | |
| AU2001270494B2 (en) | Alkynyl phenyl heteroaromatic glucokinase activators | |
| AU2001265914A1 (en) | Para-amine substituted phenylamide glucokinase activators | |
| ZA200304265B (en) | Isoindolin-1-one glucokinase activators. |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FB9A | Suspension of patent application procedure |