JP3961948B2 - テトラゾリル−フェニルアセトアミドであるグルコキナーゼ活性化物質 - Google Patents
テトラゾリル−フェニルアセトアミドであるグルコキナーゼ活性化物質 Download PDFInfo
- Publication number
- JP3961948B2 JP3961948B2 JP2002519452A JP2002519452A JP3961948B2 JP 3961948 B2 JP3961948 B2 JP 3961948B2 JP 2002519452 A JP2002519452 A JP 2002519452A JP 2002519452 A JP2002519452 A JP 2002519452A JP 3961948 B2 JP3961948 B2 JP 3961948B2
- Authority
- JP
- Japan
- Prior art keywords
- mmol
- reaction mixture
- phenyl
- methyl
- cyclopentyl
- 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
- 229940124828 glucokinase activator Drugs 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 87
- -1 perfluoro Chemical group 0.000 claims description 80
- 125000000217 alkyl group Chemical group 0.000 claims description 58
- 150000003536 tetrazoles Chemical class 0.000 claims description 54
- 229910052736 halogen Inorganic materials 0.000 claims description 42
- 238000000034 method Methods 0.000 claims description 34
- 125000001072 heteroaryl group Chemical group 0.000 claims description 33
- 229910052799 carbon Inorganic materials 0.000 claims description 30
- 150000001721 carbon Chemical group 0.000 claims description 29
- 150000002367 halogens Chemical class 0.000 claims description 29
- 150000003839 salts Chemical class 0.000 claims description 29
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 26
- 230000008569 process Effects 0.000 claims description 24
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 21
- 229910052757 nitrogen Chemical group 0.000 claims description 14
- 125000005842 heteroatom Chemical group 0.000 claims description 13
- 230000008878 coupling Effects 0.000 claims description 11
- 238000010168 coupling process Methods 0.000 claims description 11
- 238000005859 coupling reaction Methods 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- ICORAYQUZBVGMS-SFQUDFHCSA-N (e)-2-[3-chloro-4-(5-methyltetrazol-1-yl)phenyl]-3-cycloheptyl-n-(1,3-thiazol-2-yl)prop-2-enamide Chemical compound CC1=NN=NN1C1=CC=C(C(=C/C2CCCCCC2)\C(=O)NC=2SC=CN=2)C=C1Cl ICORAYQUZBVGMS-SFQUDFHCSA-N 0.000 claims description 8
- LKVCBZIKYUSOKK-LFIBNONCSA-N (e)-2-[3-chloro-4-(5-methyltetrazol-1-yl)phenyl]-3-cyclohexyl-n-(1,3-thiazol-2-yl)prop-2-enamide Chemical compound CC1=NN=NN1C1=CC=C(C(=C/C2CCCCC2)\C(=O)NC=2SC=CN=2)C=C1Cl LKVCBZIKYUSOKK-LFIBNONCSA-N 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- VLMUMBDJCAPBLI-XNTDXEJSSA-N (e)-2-[3-chloro-4-(5-methyltetrazol-1-yl)phenyl]-3-cyclopentyl-n-(1,3-thiazol-2-yl)prop-2-enamide Chemical compound CC1=NN=NN1C1=CC=C(C(=C/C2CCCC2)\C(=O)NC=2SC=CN=2)C=C1Cl VLMUMBDJCAPBLI-XNTDXEJSSA-N 0.000 claims description 7
- QIMSMHHSGVQCCP-GXDHUFHOSA-N (e)-2-[3-chloro-4-[5-(trifluoromethyl)tetrazol-1-yl]phenyl]-3-cyclohexyl-n-(1,3-thiazol-2-yl)prop-2-enamide Chemical compound FC(F)(F)C1=NN=NN1C1=CC=C(C(=C/C2CCCCC2)\C(=O)NC=2SC=CN=2)C=C1Cl QIMSMHHSGVQCCP-GXDHUFHOSA-N 0.000 claims description 7
- YJDPXMKSUFTHMS-XNTDXEJSSA-N (e)-3-cyclopentyl-2-[3-fluoro-4-(5-methyltetrazol-1-yl)phenyl]-n-(1,3-thiazol-2-yl)prop-2-enamide Chemical compound CC1=NN=NN1C1=CC=C(C(=C/C2CCCC2)\C(=O)NC=2SC=CN=2)C=C1F YJDPXMKSUFTHMS-XNTDXEJSSA-N 0.000 claims description 7
- HLIOSGRVEWBZSF-MHWRWJLKSA-N (e)-n-(5-bromo-1,3-thiazol-2-yl)-2-[3-chloro-4-(5-methyltetrazol-1-yl)phenyl]-3-cycloheptylprop-2-enamide Chemical compound CC1=NN=NN1C1=CC=C(C(=C/C2CCCCCC2)\C(=O)NC=2SC(Br)=CN=2)C=C1Cl HLIOSGRVEWBZSF-MHWRWJLKSA-N 0.000 claims description 7
- VCAPFFJIUXFVLZ-UHFFFAOYSA-N 2-[3-chloro-4-(5-methyltetrazol-1-yl)phenyl]-3-cyclopentyl-n-(1,3-thiazol-2-yl)propanamide Chemical compound CC1=NN=NN1C1=CC=C(C(CC2CCCC2)C(=O)NC=2SC=CN=2)C=C1Cl VCAPFFJIUXFVLZ-UHFFFAOYSA-N 0.000 claims description 7
- JGXAEYXCPWTPJH-UHFFFAOYSA-N 3-cyclopentyl-2-[4-(5-methyltetrazol-1-yl)-3-(trifluoromethyl)phenyl]-n-(1,3-thiazol-2-yl)propanamide Chemical compound CC1=NN=NN1C1=CC=C(C(CC2CCCC2)C(=O)NC=2SC=CN=2)C=C1C(F)(F)F JGXAEYXCPWTPJH-UHFFFAOYSA-N 0.000 claims description 7
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 7
- 125000003368 amide group Chemical group 0.000 claims description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
- RDFQPBCYHXYWEC-UHFFFAOYSA-N n-(5-bromopyridin-2-yl)-3-cyclopentyl-2-[4-(5-methyltetrazol-1-yl)-3-(trifluoromethyl)phenyl]propanamide Chemical compound CC1=NN=NN1C1=CC=C(C(CC2CCCC2)C(=O)NC=2N=CC(Br)=CC=2)C=C1C(F)(F)F RDFQPBCYHXYWEC-UHFFFAOYSA-N 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 239000001301 oxygen Substances 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 7
- 239000011593 sulfur Chemical group 0.000 claims description 7
- 125000000335 thiazolyl group Chemical group 0.000 claims description 7
- NKHVFFJXXOWCEU-LICLKQGHSA-N (e)-n-(5-bromopyridin-2-yl)-3-cyclopentyl-2-[3-fluoro-4-(5-methyltetrazol-1-yl)phenyl]prop-2-enamide Chemical compound CC1=NN=NN1C1=CC=C(C(=C/C2CCCC2)\C(=O)NC=2N=CC(Br)=CC=2)C=C1F NKHVFFJXXOWCEU-LICLKQGHSA-N 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- SBAGURZBQXASIS-UHFFFAOYSA-N n-(5-bromopyridin-2-yl)-2-[3-chloro-4-(5-methyltetrazol-1-yl)phenyl]-3-cyclopentylpropanamide Chemical compound CC1=NN=NN1C1=CC=C(C(CC2CCCC2)C(=O)NC=2N=CC(Br)=CC=2)C=C1Cl SBAGURZBQXASIS-UHFFFAOYSA-N 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- LFTGTOLTMYTROZ-LFIBNONCSA-N (e)-3-cyclopentyl-2-[3-methylsulfonyl-4-(5-methyltetrazol-1-yl)phenyl]-n-(1,3-thiazol-2-yl)prop-2-enamide Chemical compound CC1=NN=NN1C1=CC=C(C(=C/C2CCCC2)\C(=O)NC=2SC=CN=2)C=C1S(C)(=O)=O LFTGTOLTMYTROZ-LFIBNONCSA-N 0.000 claims description 5
- TVJZYYHQBQGIPR-XNTDXEJSSA-N (e)-3-cyclopentyl-2-[4-(5-methyltetrazol-1-yl)-3-(trifluoromethyl)phenyl]-n-(1,3-thiazol-2-yl)prop-2-enamide Chemical compound CC1=NN=NN1C1=CC=C(C(=C/C2CCCC2)\C(=O)NC=2SC=CN=2)C=C1C(F)(F)F TVJZYYHQBQGIPR-XNTDXEJSSA-N 0.000 claims description 5
- ADUWEZAFXRWDTE-LZYBPNLTSA-N (e)-4-cyclopentyl-2-[4-(5-methyltetrazol-1-yl)-3-(trifluoromethyl)phenyl]-n-(1,3-thiazol-2-yl)but-2-enamide Chemical compound CC1=NN=NN1C1=CC=C(C(=C/CC2CCCC2)\C(=O)NC=2SC=CN=2)C=C1C(F)(F)F ADUWEZAFXRWDTE-LZYBPNLTSA-N 0.000 claims description 5
- LPAHTBLLEJHMNM-UHFFFAOYSA-N 3-cyclopentyl-2-[3-fluoro-4-(5-methyltetrazol-1-yl)phenyl]-n-(1,3-thiazol-2-yl)propanamide Chemical compound CC1=NN=NN1C1=CC=C(C(CC2CCCC2)C(=O)NC=2SC=CN=2)C=C1F LPAHTBLLEJHMNM-UHFFFAOYSA-N 0.000 claims description 5
- PIGACGIYJAENBN-UHFFFAOYSA-N 3-cyclopentyl-2-[4-methylsulfonyl-3-(5-methyltetrazol-1-yl)phenyl]-n-(1,3-thiazol-2-yl)propanamide Chemical compound CC1=NN=NN1C1=CC(C(CC2CCCC2)C(=O)NC=2SC=CN=2)=CC=C1S(C)(=O)=O PIGACGIYJAENBN-UHFFFAOYSA-N 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- VKWFRNZZSJDCLP-UHFFFAOYSA-N n-(5-bromopyridin-2-yl)-3-cyclopentyl-2-[3-fluoro-4-(5-methyltetrazol-1-yl)phenyl]propanamide Chemical compound CC1=NN=NN1C1=CC=C(C(CC2CCCC2)C(=O)NC=2N=CC(Br)=CC=2)C=C1F VKWFRNZZSJDCLP-UHFFFAOYSA-N 0.000 claims description 5
- 150000002431 hydrogen Chemical group 0.000 claims description 4
- FUDILUPVYTXZOP-UHFFFAOYSA-N 2-[3-chloro-4-(5-methyltetrazol-1-yl)phenyl]-3-cyclohexyl-n-(1,3-thiazol-2-yl)propanamide Chemical compound CC1=NN=NN1C1=CC=C(C(CC2CCCCC2)C(=O)NC=2SC=CN=2)C=C1Cl FUDILUPVYTXZOP-UHFFFAOYSA-N 0.000 claims description 3
- IFFDTWTYMFUYKO-UHFFFAOYSA-N 2-[3-chloro-4-[5-(trifluoromethyl)tetrazol-1-yl]phenyl]-3-cyclohexyl-n-(1,3-thiazol-2-yl)propanamide Chemical compound FC(F)(F)C1=NN=NN1C1=CC=C(C(CC2CCCCC2)C(=O)NC=2SC=CN=2)C=C1Cl IFFDTWTYMFUYKO-UHFFFAOYSA-N 0.000 claims description 3
- 239000013543 active substance Substances 0.000 claims description 2
- 230000001225 therapeutic effect Effects 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 1
- 102000030595 Glucokinase Human genes 0.000 abstract description 40
- 108010021582 Glucokinase Proteins 0.000 abstract description 40
- 239000012190 activator Substances 0.000 abstract description 11
- 208000001072 type 2 diabetes mellitus Diseases 0.000 abstract description 10
- 230000003914 insulin secretion Effects 0.000 abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 588
- 239000011541 reaction mixture Substances 0.000 description 447
- 239000000243 solution Substances 0.000 description 346
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 322
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 226
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 219
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 217
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 192
- 229920006395 saturated elastomer Polymers 0.000 description 185
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 161
- 239000007787 solid Substances 0.000 description 137
- 239000010410 layer Substances 0.000 description 123
- 239000000725 suspension Substances 0.000 description 123
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 122
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 121
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 109
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 108
- 239000011780 sodium chloride Substances 0.000 description 108
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 107
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 106
- 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 88
- 238000004587 chromatography analysis Methods 0.000 description 81
- 239000000284 extract Substances 0.000 description 74
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 70
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 60
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 57
- 229910052786 argon Inorganic materials 0.000 description 54
- 239000000377 silicon dioxide Substances 0.000 description 54
- 239000000203 mixture Substances 0.000 description 50
- 239000007858 starting material Substances 0.000 description 46
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 45
- 239000012044 organic layer Substances 0.000 description 44
- 238000003756 stirring Methods 0.000 description 43
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 42
- 238000006243 chemical reaction Methods 0.000 description 42
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 40
- 239000002253 acid Substances 0.000 description 40
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 36
- 150000002894 organic compounds Chemical class 0.000 description 36
- 235000019270 ammonium chloride Nutrition 0.000 description 35
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 33
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 30
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 29
- 239000011630 iodine Substances 0.000 description 29
- 229910052740 iodine Inorganic materials 0.000 description 29
- 235000017557 sodium bicarbonate Nutrition 0.000 description 29
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 29
- 229910052725 zinc Inorganic materials 0.000 description 28
- 239000011701 zinc Substances 0.000 description 28
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 27
- 238000001914 filtration Methods 0.000 description 26
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 26
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 25
- 238000004458 analytical method Methods 0.000 description 24
- 239000003921 oil Substances 0.000 description 24
- 235000019198 oils Nutrition 0.000 description 24
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 24
- 238000009835 boiling Methods 0.000 description 23
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 23
- 238000003818 flash chromatography Methods 0.000 description 23
- 239000000499 gel Substances 0.000 description 23
- 238000004809 thin layer chromatography Methods 0.000 description 23
- 239000000543 intermediate Substances 0.000 description 20
- BJVBKJRYBWMNAB-SOFGYWHQSA-N methyl (e)-3-cyclopentyl-2-iodoprop-2-enoate Chemical compound COC(=O)C(\I)=C/C1CCCC1 BJVBKJRYBWMNAB-SOFGYWHQSA-N 0.000 description 20
- UKSZBOKPHAQOMP-SVLSSHOZSA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 UKSZBOKPHAQOMP-SVLSSHOZSA-N 0.000 description 19
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 19
- 239000012535 impurity Substances 0.000 description 19
- 230000007935 neutral effect Effects 0.000 description 19
- 150000003752 zinc compounds Chemical class 0.000 description 19
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 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 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 17
- 239000000706 filtrate Substances 0.000 description 17
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical compound NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 description 16
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 16
- 239000008103 glucose Substances 0.000 description 16
- 125000005843 halogen group Chemical group 0.000 description 16
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 15
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Substances C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 14
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 14
- 239000000908 ammonium hydroxide Substances 0.000 description 14
- 238000007796 conventional method Methods 0.000 description 14
- 238000001816 cooling Methods 0.000 description 14
- IMAKHNTVDGLIRY-UHFFFAOYSA-N methyl prop-2-ynoate Chemical compound COC(=O)C#C IMAKHNTVDGLIRY-UHFFFAOYSA-N 0.000 description 14
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 14
- 235000019345 sodium thiosulphate Nutrition 0.000 description 14
- KYQDTFZELMTOMH-UHFFFAOYSA-N 1-(2-chloro-4-iodophenyl)-5-methyltetrazole Chemical compound CC1=NN=NN1C1=CC=C(I)C=C1Cl KYQDTFZELMTOMH-UHFFFAOYSA-N 0.000 description 13
- 150000001412 amines Chemical class 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 239000004202 carbamide Substances 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 11
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 11
- 125000001424 substituent group Chemical group 0.000 description 11
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- WUDOURUBZWRKFX-UHFFFAOYSA-N 1-(2-fluoro-4-iodophenyl)-5-methyltetrazole Chemical compound CC1=NN=NN1C1=CC=C(I)C=C1F WUDOURUBZWRKFX-UHFFFAOYSA-N 0.000 description 8
- MLQLDZFAHZJCNG-UHFFFAOYSA-N 1-[4-bromo-2-(trifluoromethyl)phenyl]-5-methyltetrazole Chemical compound CC1=NN=NN1C1=CC=C(Br)C=C1C(F)(F)F MLQLDZFAHZJCNG-UHFFFAOYSA-N 0.000 description 8
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical class COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 8
- MYDAOWXYGPEPJT-UHFFFAOYSA-N 2-chloro-4-iodoaniline Chemical compound NC1=CC=C(I)C=C1Cl MYDAOWXYGPEPJT-UHFFFAOYSA-N 0.000 description 8
- 125000001246 bromo group Chemical group Br* 0.000 description 8
- BBWMASBANDIFMV-UHFFFAOYSA-N ethyl 4-phenylpiperidine-4-carboxylate;hydrochloride Chemical compound [Cl-].C=1C=CC=CC=1C1(C(=O)OCC)CC[NH2+]CC1 BBWMASBANDIFMV-UHFFFAOYSA-N 0.000 description 8
- HRBWAJGVVZVRSJ-UHFFFAOYSA-N n-(2-fluoro-4-iodophenyl)acetamide Chemical compound CC(=O)NC1=CC=C(I)C=C1F HRBWAJGVVZVRSJ-UHFFFAOYSA-N 0.000 description 8
- NJOVPNJSJCCCEC-UHFFFAOYSA-N n-[4-bromo-2-(trifluoromethyl)phenyl]acetamide Chemical compound CC(=O)NC1=CC=C(Br)C=C1C(F)(F)F NJOVPNJSJCCCEC-UHFFFAOYSA-N 0.000 description 8
- LAIZPRYFQUWUBN-UHFFFAOYSA-L nickel chloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].[Cl-].[Ni+2] LAIZPRYFQUWUBN-UHFFFAOYSA-L 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
- 239000012279 sodium borohydride Substances 0.000 description 8
- 229910000033 sodium borohydride Inorganic materials 0.000 description 8
- 239000008280 blood Substances 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 238000002844 melting Methods 0.000 description 7
- 230000008018 melting Effects 0.000 description 7
- QNJBTKSILCMUNP-VQHVLOKHSA-N methyl (e)-3-cyclohexyl-2-iodoprop-2-enoate Chemical compound COC(=O)C(\I)=C/C1CCCCC1 QNJBTKSILCMUNP-VQHVLOKHSA-N 0.000 description 7
- 239000000546 pharmaceutical excipient Substances 0.000 description 7
- YEKJYMYZUOSPPN-MDWZMJQESA-N (e)-3-cyclopentyl-2-[3-fluoro-4-(5-methyltetrazol-1-yl)phenyl]prop-2-enoic acid Chemical compound CC1=NN=NN1C1=CC=C(C(=C/C2CCCC2)\C(O)=O)C=C1F YEKJYMYZUOSPPN-MDWZMJQESA-N 0.000 description 6
- 0 C[n]1nnnc1* Chemical compound C[n]1nnnc1* 0.000 description 6
- 125000005907 alkyl ester group Chemical group 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 125000001153 fluoro group Chemical group F* 0.000 description 6
- VIZOAOZIMUGTKT-UHFFFAOYSA-N n-(2-chloro-4-iodophenyl)acetamide Chemical compound CC(=O)NC1=CC=C(I)C=C1Cl VIZOAOZIMUGTKT-UHFFFAOYSA-N 0.000 description 6
- 230000003287 optical effect Effects 0.000 description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 150000003557 thiazoles Chemical class 0.000 description 6
- BARMSAIGZLUKOE-UHFFFAOYSA-N 2-[3-chloro-4-(5-methyltetrazol-1-yl)phenyl]-3-cyclopentylpropanoic acid Chemical compound CC1=NN=NN1C1=CC=C(C(CC2CCCC2)C(O)=O)C=C1Cl BARMSAIGZLUKOE-UHFFFAOYSA-N 0.000 description 5
- LXRXDUIYNAZMOI-UHFFFAOYSA-N 3-cyclopentyl-2-[4-(5-methyltetrazol-1-yl)-3-(trifluoromethyl)phenyl]propanoic acid Chemical compound CC1=NN=NN1C1=CC=C(C(CC2CCCC2)C(O)=O)C=C1C(F)(F)F LXRXDUIYNAZMOI-UHFFFAOYSA-N 0.000 description 5
- XZGLNCKSNVGDNX-UHFFFAOYSA-N 5-methyl-2h-tetrazole Chemical compound CC=1N=NNN=1 XZGLNCKSNVGDNX-UHFFFAOYSA-N 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 125000001309 chloro group Chemical group Cl* 0.000 description 5
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000011534 incubation Methods 0.000 description 5
- UKAAVIBZUZOROZ-UHFFFAOYSA-N 1-(2-chloro-4-iodophenyl)-5-(trifluoromethyl)tetrazole Chemical compound FC(F)(F)C1=NN=NN1C1=CC=C(I)C=C1Cl UKAAVIBZUZOROZ-UHFFFAOYSA-N 0.000 description 4
- CUMTUBVTKOYYOU-UHFFFAOYSA-N 2-fluoro-4-iodoaniline Chemical compound NC1=CC=C(I)C=C1F CUMTUBVTKOYYOU-UHFFFAOYSA-N 0.000 description 4
- PHXGKHTWEOPCEW-UHFFFAOYSA-N 4-bromo-2-(trifluoromethyl)aniline Chemical compound NC1=CC=C(Br)C=C1C(F)(F)F PHXGKHTWEOPCEW-UHFFFAOYSA-N 0.000 description 4
- WGOLHUGPTDEKCF-UHFFFAOYSA-N 5-bromopyridin-2-amine Chemical compound NC1=CC=C(Br)C=N1 WGOLHUGPTDEKCF-UHFFFAOYSA-N 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- XGEGHDBEHXKFPX-UHFFFAOYSA-N N-methylthiourea Natural products CNC(N)=O XGEGHDBEHXKFPX-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- LOXORFRCPXUORP-UHFFFAOYSA-N bromo-Cycloheptane Chemical compound BrC1CCCCCC1 LOXORFRCPXUORP-UHFFFAOYSA-N 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- WQOXQRCZOLPYPM-UHFFFAOYSA-N dimethyl disulfide Chemical compound CSSC WQOXQRCZOLPYPM-UHFFFAOYSA-N 0.000 description 4
- 230000004153 glucose metabolism Effects 0.000 description 4
- 210000003494 hepatocyte Anatomy 0.000 description 4
- 125000002346 iodo group Chemical group I* 0.000 description 4
- WZGHPZAWYONZRF-NTEUORMPSA-N methyl (e)-2-[3-chloro-4-(5-methyltetrazol-1-yl)phenyl]-3-cyclopentylprop-2-enoate Chemical compound C=1C=C(N2C(=NN=N2)C)C(Cl)=CC=1/C(C(=O)OC)=C\C1CCCC1 WZGHPZAWYONZRF-NTEUORMPSA-N 0.000 description 4
- ZAAIOMLFPNNHMX-CSKARUKUSA-N methyl (e)-3-cycloheptyl-2-iodoprop-2-enoate Chemical compound COC(=O)C(\I)=C/C1CCCCCC1 ZAAIOMLFPNNHMX-CSKARUKUSA-N 0.000 description 4
- LSBITXRRZBZOHT-NTEUORMPSA-N methyl (e)-3-cyclopentyl-2-[4-(5-methyltetrazol-1-yl)-3-(trifluoromethyl)phenyl]prop-2-enoate Chemical compound C=1C=C(N2C(=NN=N2)C)C(C(F)(F)F)=CC=1/C(C(=O)OC)=C\C1CCCC1 LSBITXRRZBZOHT-NTEUORMPSA-N 0.000 description 4
- 229920005862 polyol Polymers 0.000 description 4
- 150000003077 polyols Chemical class 0.000 description 4
- 150000003222 pyridines Chemical class 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- SZLKMRIXLMTLOP-UHFFFAOYSA-N 3-cyclopentyl-2-[3-fluoro-4-(5-methyltetrazol-1-yl)phenyl]propanoic acid Chemical compound CC1=NN=NN1C1=CC=C(C(CC2CCCC2)C(O)=O)C=C1F SZLKMRIXLMTLOP-UHFFFAOYSA-N 0.000 description 3
- OOQBPGSJGVKPHP-UHFFFAOYSA-N 3-cyclopentyl-n-(methylcarbamoyl)-2-[4-(5-methyltetrazol-1-yl)-3-(trifluoromethyl)phenyl]propanamide Chemical compound C=1C=C(N2C(=NN=N2)C)C(C(F)(F)F)=CC=1C(C(=O)NC(=O)NC)CC1CCCC1 OOQBPGSJGVKPHP-UHFFFAOYSA-N 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 3
- 102000005548 Hexokinase Human genes 0.000 description 3
- 108700040460 Hexokinases Proteins 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
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 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
- 239000008120 corn starch Substances 0.000 description 3
- 206010012601 diabetes mellitus Diseases 0.000 description 3
- 239000008298 dragée Substances 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- FUCOMWZKWIEKRK-UHFFFAOYSA-N iodocyclohexane Chemical compound IC1CCCCC1 FUCOMWZKWIEKRK-UHFFFAOYSA-N 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 229910052749 magnesium Inorganic materials 0.000 description 3
- HIISIOCIWYIICR-UKTHLTGXSA-N methyl (e)-2-[3-chloro-4-[5-(trifluoromethyl)tetrazol-1-yl]phenyl]-3-cyclohexylprop-2-enoate Chemical compound C=1C=C(N2C(=NN=N2)C(F)(F)F)C(Cl)=CC=1/C(C(=O)OC)=C\C1CCCCC1 HIISIOCIWYIICR-UKTHLTGXSA-N 0.000 description 3
- TZFHEVKMXBSSLX-NTEUORMPSA-N methyl (e)-3-cyclopentyl-2-[3-fluoro-4-(5-methyltetrazol-1-yl)phenyl]prop-2-enoate Chemical compound C=1C=C(N2C(=NN=N2)C)C(F)=CC=1/C(C(=O)OC)=C\C1CCCC1 TZFHEVKMXBSSLX-NTEUORMPSA-N 0.000 description 3
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 3
- XGEGHDBEHXKFPX-NJFSPNSNSA-N methylurea Chemical compound [14CH3]NC(N)=O XGEGHDBEHXKFPX-NJFSPNSNSA-N 0.000 description 3
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 3
- 229910001948 sodium oxide Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 125000004523 tetrazol-1-yl group Chemical group N1(N=NN=C1)* 0.000 description 3
- 150000003573 thiols Chemical class 0.000 description 3
- FMCAFXHLMUOIGG-JTJHWIPRSA-N (2s)-2-[[(2r)-2-[[(2s)-2-[[(2r)-2-formamido-3-sulfanylpropanoyl]amino]-3-methylbutanoyl]amino]-3-(4-hydroxy-2,5-dimethylphenyl)propanoyl]amino]-4-methylsulfanylbutanoic acid Chemical compound O=CN[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(=O)N[C@@H](CCSC)C(O)=O)CC1=CC(C)=C(O)C=C1C FMCAFXHLMUOIGG-JTJHWIPRSA-N 0.000 description 2
- QZOPFSKSPDCOSN-XNTDXEJSSA-N (e)-2-[3-chloro-4-(5-methyltetrazol-1-yl)phenyl]-3-cycloheptylprop-2-enoic acid Chemical compound CC1=NN=NN1C1=CC=C(C(=C/C2CCCCCC2)\C(O)=O)C=C1Cl QZOPFSKSPDCOSN-XNTDXEJSSA-N 0.000 description 2
- KKSIHNCDBOMQRF-NTEUORMPSA-N (e)-3-cyclopentyl-2-[3-fluoro-4-(5-methyltetrazol-1-yl)phenyl]-n-(methylcarbamoyl)prop-2-enamide Chemical compound C=1C=C(N2C(=NN=N2)C)C(F)=CC=1/C(C(=O)NC(=O)NC)=C\C1CCCC1 KKSIHNCDBOMQRF-NTEUORMPSA-N 0.000 description 2
- KEAZDWYDDIPGEL-UHFFFAOYSA-N 1-(4-bromo-2-methylsulfanylphenyl)-5-methyltetrazole Chemical compound CSC1=CC(Br)=CC=C1N1C(C)=NN=N1 KEAZDWYDDIPGEL-UHFFFAOYSA-N 0.000 description 2
- BVXXQUZRWNCYJE-UHFFFAOYSA-N 1-(4-bromo-2-methylsulfonylphenyl)-5-methyltetrazole Chemical compound CC1=NN=NN1C1=CC=C(Br)C=C1S(C)(=O)=O BVXXQUZRWNCYJE-UHFFFAOYSA-N 0.000 description 2
- KJEKOKLWEOLVRU-UHFFFAOYSA-N 1-(4-bromo-2-nitrophenyl)-5-methyltetrazole Chemical compound CC1=NN=NN1C1=CC=C(Br)C=C1[N+]([O-])=O KJEKOKLWEOLVRU-UHFFFAOYSA-N 0.000 description 2
- UCZUGBXCHHVKEH-UHFFFAOYSA-N 1-(5-bromo-2-methylsulfonylphenyl)-5-methyltetrazole Chemical compound CC1=NN=NN1C1=CC(Br)=CC=C1S(C)(=O)=O UCZUGBXCHHVKEH-UHFFFAOYSA-N 0.000 description 2
- 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 2
- KRSYIQXACUTTRM-UHFFFAOYSA-N 2-[3-chloro-4-(5-methyltetrazol-1-yl)phenyl]-3-cyclohexylpropanoic acid Chemical compound CC1=NN=NN1C1=CC=C(C(CC2CCCCC2)C(O)=O)C=C1Cl KRSYIQXACUTTRM-UHFFFAOYSA-N 0.000 description 2
- PLTGOPOOWJCRCW-UHFFFAOYSA-N 2-[3-chloro-4-(5-methyltetrazol-1-yl)phenyl]-3-cyclopentyl-n-(methylcarbamoyl)propanamide Chemical compound C=1C=C(N2C(=NN=N2)C)C(Cl)=CC=1C(C(=O)NC(=O)NC)CC1CCCC1 PLTGOPOOWJCRCW-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
- MMOJCDVXHLYZAE-UHFFFAOYSA-N 3-cyclopentyl-2-[4-methylsulfonyl-3-(5-methyltetrazol-1-yl)phenyl]propanoic acid Chemical compound CC1=NN=NN1C1=CC(C(CC2CCCC2)C(O)=O)=CC=C1S(C)(=O)=O MMOJCDVXHLYZAE-UHFFFAOYSA-N 0.000 description 2
- RFQIQDIAWTUKKG-UHFFFAOYSA-N 4-bromo-1-methylsulfanyl-2-nitrobenzene Chemical compound CSC1=CC=C(Br)C=C1[N+]([O-])=O RFQIQDIAWTUKKG-UHFFFAOYSA-N 0.000 description 2
- GWDGHKCIKJPPOP-UHFFFAOYSA-N 4-bromo-1-methylsulfonyl-2-nitrobenzene Chemical compound CS(=O)(=O)C1=CC=C(Br)C=C1[N+]([O-])=O GWDGHKCIKJPPOP-UHFFFAOYSA-N 0.000 description 2
- ZCWBZRBJSPWUPG-UHFFFAOYSA-N 4-bromo-2-nitroaniline Chemical compound NC1=CC=C(Br)C=C1[N+]([O-])=O ZCWBZRBJSPWUPG-UHFFFAOYSA-N 0.000 description 2
- PTVHVWIVGQJNPY-UHFFFAOYSA-N 5-bromo-2-(5-methyltetrazol-1-yl)aniline Chemical compound CC1=NN=NN1C1=CC=C(Br)C=C1N PTVHVWIVGQJNPY-UHFFFAOYSA-N 0.000 description 2
- KWTCKSCLEBBNDI-UHFFFAOYSA-N 5-bromo-2-methylsulfonylaniline Chemical compound CS(=O)(=O)C1=CC=C(Br)C=C1N KWTCKSCLEBBNDI-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 238000006418 Brown reaction Methods 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- FCUSBNCDGIMFSR-UHFFFAOYSA-N ClC=1C=C(C=CC1N1N=NN=C1C(F)(F)F)C(C(=O)NC=1SC=CN1)CC1CCCC1 Chemical compound ClC=1C=C(C=CC1N1N=NN=C1C(F)(F)F)C(C(=O)NC=1SC=CN1)CC1CCCC1 FCUSBNCDGIMFSR-UHFFFAOYSA-N 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
- 239000001828 Gelatine Substances 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
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 208000013016 Hypoglycemia Diseases 0.000 description 2
- 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 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-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
- KMAQJJKRGAFLBH-UHFFFAOYSA-M [Br-].[Mg+]C1CCCCCC1 Chemical compound [Br-].[Mg+]C1CCCCCC1 KMAQJJKRGAFLBH-UHFFFAOYSA-M 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 150000001448 anilines Chemical class 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 150000001540 azides Chemical class 0.000 description 2
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- LDHQCZJRKDOVOX-NSCUHMNNSA-N crotonic acid Chemical compound C\C=C\C(O)=O LDHQCZJRKDOVOX-NSCUHMNNSA-N 0.000 description 2
- 239000012954 diazonium Substances 0.000 description 2
- 150000001989 diazonium salts Chemical class 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000003925 fat Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000007789 gas Substances 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
- 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
- 150000002391 heterocyclic compounds Chemical class 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000000338 in vitro 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
- OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-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
- 238000005259 measurement Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- IEKRFHFYAMUWQK-LFIBNONCSA-N methyl (e)-2-[3-chloro-4-(5-methyltetrazol-1-yl)phenyl]-3-cycloheptylprop-2-enoate Chemical compound C=1C=C(N2C(=NN=N2)C)C(Cl)=CC=1/C(C(=O)OC)=C\C1CCCCCC1 IEKRFHFYAMUWQK-LFIBNONCSA-N 0.000 description 2
- HABHISJDRYEPFC-XNTDXEJSSA-N methyl (e)-3-cyclopentyl-2-[3-methylsulfonyl-4-(5-methyltetrazol-1-yl)phenyl]prop-2-enoate Chemical compound C=1C=C(N2C(=NN=N2)C)C(S(C)(=O)=O)=CC=1/C(C(=O)OC)=C\C1CCCC1 HABHISJDRYEPFC-XNTDXEJSSA-N 0.000 description 2
- DSNDNALOCLTFDU-OQLLNIDSSA-N methyl (e)-4-cyclopentyl-2-[4-(5-methyltetrazol-1-yl)-3-(trifluoromethyl)phenyl]but-2-enoate Chemical compound C=1C=C(N2C(=NN=N2)C)C(C(F)(F)F)=CC=1/C(C(=O)OC)=C\CC1CCCC1 DSNDNALOCLTFDU-OQLLNIDSSA-N 0.000 description 2
- MUFUHQXBLCHYNI-VQHVLOKHSA-N methyl (e)-4-cyclopentyl-2-iodobut-2-enoate Chemical compound COC(=O)C(\I)=C/CC1CCCC1 MUFUHQXBLCHYNI-VQHVLOKHSA-N 0.000 description 2
- IECBXFVNWYYRAW-UHFFFAOYSA-N methyl 2-[3-chloro-4-(5-methyltetrazol-1-yl)phenyl]-3-cyclohexylpropanoate Chemical compound C=1C=C(N2C(=NN=N2)C)C(Cl)=CC=1C(C(=O)OC)CC1CCCCC1 IECBXFVNWYYRAW-UHFFFAOYSA-N 0.000 description 2
- MWGAMAOBFVQDEL-UHFFFAOYSA-N methyl 2-[3-chloro-4-(5-methyltetrazol-1-yl)phenyl]-3-cyclopentylpropanoate Chemical compound C=1C=C(N2C(=NN=N2)C)C(Cl)=CC=1C(C(=O)OC)CC1CCCC1 MWGAMAOBFVQDEL-UHFFFAOYSA-N 0.000 description 2
- DALJDSPLTWXPNV-UHFFFAOYSA-N methyl 2-[3-chloro-4-[5-(trifluoromethyl)tetrazol-1-yl]phenyl]-3-cyclohexylpropanoate Chemical compound C=1C=C(N2C(=NN=N2)C(F)(F)F)C(Cl)=CC=1C(C(=O)OC)CC1CCCCC1 DALJDSPLTWXPNV-UHFFFAOYSA-N 0.000 description 2
- WAIGZHUIHIQTHS-UHFFFAOYSA-N methyl 3-cyclopentyl-2-[3-fluoro-4-(5-methyltetrazol-1-yl)phenyl]propanoate Chemical compound C=1C=C(N2C(=NN=N2)C)C(F)=CC=1C(C(=O)OC)CC1CCCC1 WAIGZHUIHIQTHS-UHFFFAOYSA-N 0.000 description 2
- ZFRVGEJGJPYLFL-UHFFFAOYSA-N methyl 3-cyclopentyl-2-[4-(5-methyltetrazol-1-yl)-3-(trifluoromethyl)phenyl]propanoate Chemical compound C=1C=C(N2C(=NN=N2)C)C(C(F)(F)F)=CC=1C(C(=O)OC)CC1CCCC1 ZFRVGEJGJPYLFL-UHFFFAOYSA-N 0.000 description 2
- DKBNVGOWHNOALZ-UHFFFAOYSA-N methyl 3-cyclopentylprop-2-enoate Chemical compound COC(=O)C=CC1CCCC1 DKBNVGOWHNOALZ-UHFFFAOYSA-N 0.000 description 2
- GJQQHYNZZYZIKE-UHFFFAOYSA-N n-(1,3-thiazol-2-yl)prop-2-enamide Chemical compound C=CC(=O)NC1=NC=CS1 GJQQHYNZZYZIKE-UHFFFAOYSA-N 0.000 description 2
- GUBNCRISSRANNO-UHFFFAOYSA-N n-(4-bromo-2-nitrophenyl)acetamide Chemical compound CC(=O)NC1=CC=C(Br)C=C1[N+]([O-])=O GUBNCRISSRANNO-UHFFFAOYSA-N 0.000 description 2
- SBLLYQQDCBOFIP-UHFFFAOYSA-N n-(5-bromo-2-methylsulfonylphenyl)acetamide Chemical compound CC(=O)NC1=CC(Br)=CC=C1S(C)(=O)=O SBLLYQQDCBOFIP-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 2
- 229940080818 propionamide Drugs 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 150000003852 triazoles Chemical class 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 239000001993 wax Substances 0.000 description 2
- FMCAFXHLMUOIGG-IWFBPKFRSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2r)-2-formamido-3-sulfanylpropanoyl]amino]-3-methylbutanoyl]amino]-3-(4-hydroxy-2,5-dimethylphenyl)propanoyl]amino]-4-methylsulfanylbutanoic acid Chemical compound O=CN[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCSC)C(O)=O)CC1=CC(C)=C(O)C=C1C FMCAFXHLMUOIGG-IWFBPKFRSA-N 0.000 description 1
- AHPAGNPUDJANNL-NTEUORMPSA-N (e)-2-[3-chloro-4-(5-methyltetrazol-1-yl)phenyl]-3-cyclohexylprop-2-enoic acid Chemical compound CC1=NN=NN1C1=CC=C(C(=C/C2CCCCC2)\C(O)=O)C=C1Cl AHPAGNPUDJANNL-NTEUORMPSA-N 0.000 description 1
- FNOYGXWVJJAALB-MDWZMJQESA-N (e)-2-[3-chloro-4-(5-methyltetrazol-1-yl)phenyl]-3-cyclopentylprop-2-enoic acid Chemical compound CC1=NN=NN1C1=CC=C(C(=C/C2CCCC2)\C(O)=O)C=C1Cl FNOYGXWVJJAALB-MDWZMJQESA-N 0.000 description 1
- NTEDFCJECXCWNN-XYOKQWHBSA-N (e)-2-[3-chloro-4-[5-(trifluoromethyl)tetrazol-1-yl]phenyl]-3-cyclohexylprop-2-enoic acid Chemical compound C=1C=C(N2C(=NN=N2)C(F)(F)F)C(Cl)=CC=1/C(C(=O)O)=C\C1CCCCC1 NTEDFCJECXCWNN-XYOKQWHBSA-N 0.000 description 1
- MSYREWJFFYMOSC-NTEUORMPSA-N (e)-3-cyclopentyl-2-[3-methylsulfonyl-4-(5-methyltetrazol-1-yl)phenyl]prop-2-enoic acid Chemical compound CC1=NN=NN1C1=CC=C(C(=C/C2CCCC2)\C(O)=O)C=C1S(C)(=O)=O MSYREWJFFYMOSC-NTEUORMPSA-N 0.000 description 1
- LXLMZIHLHGTYIJ-MDWZMJQESA-N (e)-3-cyclopentyl-2-[4-(5-methyltetrazol-1-yl)-3-(trifluoromethyl)phenyl]prop-2-enoic acid Chemical compound CC1=NN=NN1C1=CC=C(C(=C/C2CCCC2)\C(O)=O)C=C1C(F)(F)F LXLMZIHLHGTYIJ-MDWZMJQESA-N 0.000 description 1
- YBDCRMOHQUUUPI-RIYZIHGNSA-N (e)-4-cyclopentyl-2-[4-(5-methyltetrazol-1-yl)-3-(trifluoromethyl)phenyl]but-2-enoic acid Chemical compound CC1=NN=NN1C1=CC=C(C(=C/CC2CCCC2)\C(O)=O)C=C1C(F)(F)F YBDCRMOHQUUUPI-RIYZIHGNSA-N 0.000 description 1
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- FFJWPGGBISIFHI-UHFFFAOYSA-N 1-methylnaphthalen-2-amine Chemical compound C1=CC=C2C(C)=C(N)C=CC2=C1 FFJWPGGBISIFHI-UHFFFAOYSA-N 0.000 description 1
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 description 1
- OBTZDIRUQWFRFZ-UHFFFAOYSA-N 2-(5-methylfuran-2-yl)-n-(4-methylphenyl)quinoline-4-carboxamide Chemical compound O1C(C)=CC=C1C1=CC(C(=O)NC=2C=CC(C)=CC=2)=C(C=CC=C2)C2=N1 OBTZDIRUQWFRFZ-UHFFFAOYSA-N 0.000 description 1
- MIKWGVILPPPIET-UHFFFAOYSA-N 2-[3-chloro-4-[5-(trifluoromethyl)tetrazol-1-yl]phenyl]-3-cyclohexylpropanoic acid Chemical compound C=1C=C(N2C(=NN=N2)C(F)(F)F)C(Cl)=CC=1C(C(=O)O)CC1CCCCC1 MIKWGVILPPPIET-UHFFFAOYSA-N 0.000 description 1
- ULQQGOGMQRGFFR-UHFFFAOYSA-N 2-chlorobenzenecarboperoxoic acid Chemical compound OOC(=O)C1=CC=CC=C1Cl ULQQGOGMQRGFFR-UHFFFAOYSA-N 0.000 description 1
- FQHUWSPRTMWLFA-UHFFFAOYSA-N 2-cyclohexylprop-2-enoic acid Chemical compound OC(=O)C(=C)C1CCCCC1 FQHUWSPRTMWLFA-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
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-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
- 102100031126 6-phosphogluconolactonase Human genes 0.000 description 1
- 108010029731 6-phosphogluconolactonase Proteins 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
- 210000002237 B-cell of pancreatic islet Anatomy 0.000 description 1
- 239000004342 Benzoyl peroxide Substances 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- 238000011746 C57BL/6J (JAX™ mouse strain) Methods 0.000 description 1
- 235000001258 Cinchona calisaya Nutrition 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-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
- 241000588724 Escherichia coli Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 108010018962 Glucosephosphate Dehydrogenase Proteins 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
- 239000007818 Grignard reagent Substances 0.000 description 1
- 241000282412 Homo Species 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
- FIWILGQIZHDAQG-UHFFFAOYSA-N NC1=C(C(=O)NCC2=CC=C(C=C2)OCC(F)(F)F)C=C(C(=N1)N)N1N=C(N=C1)C1(CC1)C(F)(F)F Chemical compound NC1=C(C(=O)NCC2=CC=C(C=C2)OCC(F)(F)F)C=C(C(=N1)N)N1N=C(N=C1)C1(CC1)C(F)(F)F FIWILGQIZHDAQG-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-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
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 1
- 229920002684 Sepharose Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 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
- JVVXZOOGOGPDRZ-SLFFLAALSA-N [(1R,4aS,10aR)-1,4a-dimethyl-7-propan-2-yl-2,3,4,9,10,10a-hexahydrophenanthren-1-yl]methanamine Chemical compound NC[C@]1(C)CCC[C@]2(C)C3=CC=C(C(C)C)C=C3CC[C@H]21 JVVXZOOGOGPDRZ-SLFFLAALSA-N 0.000 description 1
- QBBRWBVKFOXJCQ-UHFFFAOYSA-N [Cu]C=C Chemical compound [Cu]C=C QBBRWBVKFOXJCQ-UHFFFAOYSA-N 0.000 description 1
- BOAFHDFCBONIDC-UHFFFAOYSA-N [Zn]C=C Chemical compound [Zn]C=C BOAFHDFCBONIDC-UHFFFAOYSA-N 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 125000003647 acryloyl group Chemical group O=C([*])C([H])=C([H])[H] 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 235000019400 benzoyl peroxide Nutrition 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003638 chemical reducing agent Substances 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
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 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 1
- 230000003247 decreasing effect Effects 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
- 239000002552 dosage form Substances 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
- 238000010931 ester hydrolysis Methods 0.000 description 1
- UFBFCSKCPCZCLE-UHFFFAOYSA-N ethyl 5-(bromomethyl)-1,3-thiazole-2-carboxylate Chemical compound CCOC(=O)C1=NC=C(CBr)S1 UFBFCSKCPCZCLE-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 238000003304 gavage Methods 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
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 150000002366 halogen compounds Chemical class 0.000 description 1
- 125000006343 heptafluoro propyl group Chemical group 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 150000002466 imines 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
- 229960004903 invert sugar Drugs 0.000 description 1
- DUMSKQUKLVSSII-UHFFFAOYSA-N iodomethylcyclopentane Chemical compound ICC1CCCC1 DUMSKQUKLVSSII-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000004777 loss-of-function mutation Effects 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate 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
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- AGJSNMGHAVDLRQ-HUUJSLGLSA-N methyl (2s)-2-[[(2r)-2-[[(2s)-2-[[(2r)-2-amino-3-sulfanylpropanoyl]amino]-3-methylbutanoyl]amino]-3-(4-hydroxy-2,3-dimethylphenyl)propanoyl]amino]-4-methylsulfanylbutanoate Chemical compound SC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(=O)N[C@@H](CCSC)C(=O)OC)CC1=CC=C(O)C(C)=C1C AGJSNMGHAVDLRQ-HUUJSLGLSA-N 0.000 description 1
- UIUDQOBQXQRGHU-XNTDXEJSSA-N methyl (e)-2-[3-chloro-4-(5-methyltetrazol-1-yl)phenyl]-3-cyclohexylprop-2-enoate Chemical compound C=1C=C(N2C(=NN=N2)C)C(Cl)=CC=1/C(C(=O)OC)=C\C1CCCCC1 UIUDQOBQXQRGHU-XNTDXEJSSA-N 0.000 description 1
- GWCAJVOBGXTVDM-XNTDXEJSSA-N methyl (e)-3-cyclopentyl-2-[4-methylsulfonyl-3-(5-methyltetrazol-1-yl)phenyl]prop-2-enoate Chemical compound C=1C=C(S(C)(=O)=O)C(N2C(=NN=N2)C)=CC=1/C(C(=O)OC)=C\C1CCCC1 GWCAJVOBGXTVDM-XNTDXEJSSA-N 0.000 description 1
- XKLAFWWDQPGTLE-UHFFFAOYSA-N methyl 3-cyclohexylprop-2-enoate Chemical compound COC(=O)C=CC1CCCCC1 XKLAFWWDQPGTLE-UHFFFAOYSA-N 0.000 description 1
- WFESBDIZGBZIHQ-UHFFFAOYSA-N methyl 3-cyclopentyl-2-[4-methylsulfonyl-3-(5-methyltetrazol-1-yl)phenyl]propanoate Chemical compound C=1C=C(S(C)(=O)=O)C(N2C(=NN=N2)C)=CC=1C(C(=O)OC)CC1CCCC1 WFESBDIZGBZIHQ-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 229910052759 nickel Inorganic materials 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
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- 150000002829 nitrogen Chemical class 0.000 description 1
- JVJQPDTXIALXOG-UHFFFAOYSA-N nitryl fluoride Chemical compound [O-][N+](F)=O JVJQPDTXIALXOG-UHFFFAOYSA-N 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
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000008012 organic excipient Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-N propynoic acid Chemical compound OC(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000002904 solvent Substances 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
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 125000004434 sulfur atom Chemical group 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
- 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
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
-
- 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)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Emergency Medicine (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Endocrinology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US22549400P | 2000-08-15 | 2000-08-15 | |
| PCT/EP2001/009207 WO2002014312A1 (en) | 2000-08-15 | 2001-08-09 | Tetrazolyl-phenyl acetamide glucokinase activators |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2004506632A JP2004506632A (ja) | 2004-03-04 |
| JP2004506632A5 JP2004506632A5 (enExample) | 2005-03-17 |
| JP3961948B2 true JP3961948B2 (ja) | 2007-08-22 |
Family
ID=22845106
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2002519452A Expired - Fee Related JP3961948B2 (ja) | 2000-08-15 | 2001-08-09 | テトラゾリル−フェニルアセトアミドであるグルコキナーゼ活性化物質 |
Country Status (20)
| Country | Link |
|---|---|
| US (3) | US6369232B1 (enExample) |
| EP (1) | EP1311504B1 (enExample) |
| JP (1) | JP3961948B2 (enExample) |
| KR (1) | KR100518061B1 (enExample) |
| CN (1) | CN1209362C (enExample) |
| AR (1) | AR031718A1 (enExample) |
| AT (1) | ATE297921T1 (enExample) |
| AU (2) | AU8399801A (enExample) |
| BR (1) | BR0113312A (enExample) |
| CA (1) | CA2419416C (enExample) |
| DE (1) | DE60111540T2 (enExample) |
| DK (1) | DK1311504T3 (enExample) |
| ES (1) | ES2243541T3 (enExample) |
| MX (1) | MXPA03001275A (enExample) |
| PA (1) | PA8525201A1 (enExample) |
| PE (1) | PE20020386A1 (enExample) |
| PT (1) | PT1311504E (enExample) |
| UY (1) | UY26885A1 (enExample) |
| WO (1) | WO2002014312A1 (enExample) |
| ZA (1) | ZA200300904B (enExample) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101918363B (zh) * | 2008-01-18 | 2012-09-05 | 安斯泰来制药株式会社 | 苯乙酰胺衍生物 |
Families Citing this family (36)
| 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 |
| US7078423B2 (en) * | 2002-07-18 | 2006-07-18 | Inotek Pharmaceuticals Corporation | 5-Aryltetrazole compounds, compositions thereof, and uses therefor |
| US7087631B2 (en) * | 2002-07-18 | 2006-08-08 | Inotek Pharmaceuticals Corporation | Aryltetrazole compounds, and compositions thereof |
| NZ539013A (en) | 2002-10-03 | 2007-05-31 | 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 |
| US7132425B2 (en) | 2002-12-12 | 2006-11-07 | Hoffmann-La Roche Inc. | 5-substituted-six-membered heteroaromatic glucokinase activators |
| AU2003294376A1 (en) * | 2003-01-06 | 2004-08-10 | Eli Lilly And Company | Heteroaryl compounds |
| EP1594863A1 (en) * | 2003-02-11 | 2005-11-16 | Prosidion Limited | Tri(cyclo) substituted amide glucokinase activator compounds |
| PL378117A1 (pl) * | 2003-02-11 | 2006-03-06 | Prosidion Limited | Tricyklopodstawione związki amidowe |
| KR20070006816A (ko) | 2004-04-02 | 2007-01-11 | 노파르티스 아게 | 티아졸로피리딘 유도체, 이를 함유하는 제약 조성물 및글루코키나제 매개형 증상의 치료 방법 |
| KR100830007B1 (ko) | 2004-04-02 | 2008-05-15 | 노파르티스 아게 | 2형 당뇨병 치료에 유용한 글루코키나제 활성화제로서의술폰아미드-티아졸피리딘 유도체 |
| NZ564608A (en) | 2005-07-09 | 2009-09-25 | Astrazeneca Ab | Heteroaryl benzamide derivatives for use as GLK activators in the treatment of diabetes |
| CN101218237B (zh) * | 2005-07-11 | 2012-03-28 | 田边三菱制药株式会社 | 肟衍生物及其制备方法 |
| EP1921074A1 (en) | 2005-08-31 | 2008-05-14 | Astellas Pharma Inc. | Thiazole derivative |
| JP2007063225A (ja) * | 2005-09-01 | 2007-03-15 | Takeda Chem Ind Ltd | イミダゾピリジン化合物 |
| AU2006299091A1 (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 |
| GT200600429A (es) | 2005-09-30 | 2007-04-30 | Compuestos organicos | |
| GT200600428A (es) | 2005-09-30 | 2007-05-21 | Compuestos organicos | |
| BRPI0618062A2 (pt) * | 2005-11-03 | 2011-08-16 | Prosidion Ltd | composto ou um sal farmaceuticamente aceitável do mesmo, composição farmacêutica, uso de um composto ou um sal farmaceuticamente aceitável do mesmo, e, processo para a preparação de um composto |
| US20070197532A1 (en) * | 2005-11-18 | 2007-08-23 | Cao Sheldon X | Glucokinase activators |
| ES2381864T3 (es) * | 2005-12-15 | 2012-06-01 | Nihon Nohyaku Co., Ltd. | Derivado de ftalamida, pesticida agrícola u hortícola y utilización del pesticida |
| JP5302012B2 (ja) | 2006-03-08 | 2013-10-02 | 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 |
| PE20080251A1 (es) | 2006-05-04 | 2008-04-25 | Boehringer Ingelheim Int | Usos de inhibidores de dpp iv |
| ATE522518T1 (de) | 2006-05-31 | 2011-09-15 | Takeda San Diego Inc | Indazol- und isoindolderivate als glucokinaseaktivierende stoffe |
| US7910747B2 (en) * | 2006-07-06 | 2011-03-22 | Bristol-Myers Squibb Company | Phosphonate and phosphinate pyrazolylamide glucokinase activators |
| US7902248B2 (en) | 2006-12-14 | 2011-03-08 | Hoffmann-La Roche Inc. | Oxime glucokinase activators |
| WO2008079787A2 (en) | 2006-12-20 | 2008-07-03 | Takeda San Diego, Inc. | Glucokinase activators |
| TW200831081A (en) * | 2006-12-25 | 2008-08-01 | Kyorin Seiyaku Kk | Glucokinase activator |
| US8314247B2 (en) * | 2007-01-10 | 2012-11-20 | Mitsubishi Tanabe Pharma Corporation | Hydrazone derivative |
| KR20090121376A (ko) | 2007-03-07 | 2009-11-25 | 교린 세이야꾸 가부시키 가이샤 | 글루코키나아제 활성화 물질 |
| US8173645B2 (en) * | 2007-03-21 | 2012-05-08 | Takeda San Diego, Inc. | Glucokinase activators |
| AU2008310519B2 (en) * | 2007-10-08 | 2013-05-02 | Advinus Therapeutics Private Limited | Acetamide derivatives as glucokinase activators, their process and medicinal applications |
| AR070107A1 (es) * | 2008-01-15 | 2010-03-17 | Lilly Co Eli | R-2-(4-ciclopropansulfonil-fenil)-n-pirazin-2-il-3-(tetrahidropiran-4-il)-propionamida en forma cristalina, composicion farmaceutica que la comprende y su uso para la manufactura de un medicamento util para la prevencion o tratamiento de hiperglicemia |
| CA2722733C (en) * | 2008-04-28 | 2016-02-23 | Kyorin Pharmaceutical Co., Ltd. | Cyclopentylacrylamide derivative |
| CA2800498C (en) | 2010-03-31 | 2021-11-16 | The Scripps Research Institute | Reprogramming cells |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3776917A (en) * | 1972-06-05 | 1973-12-04 | Schering Corp | 2-amino-6-phenalkyl-aminopyridines and derivatives thereof |
| GB8909574D0 (en) | 1989-04-26 | 1989-06-14 | Ici Plc | Chemical process |
| US5859052A (en) * | 1993-01-14 | 1999-01-12 | G. D. Searle & Co. | Fatty acid analogs and prodrugs |
| US5461049A (en) * | 1994-05-27 | 1995-10-24 | Warner-Lambert Company | Amide tetrazole ACAT inhibitors |
| US5468867A (en) * | 1994-05-27 | 1995-11-21 | Syntex (U.S.A.) Inc. | Process for preparing1-butyl-2-[2'-(2H-tetrazol-5-yl)biphenyl-4-ylmethyl1-1H-indole-3-carboxylic acid |
| PL334833A1 (en) * | 1997-01-28 | 2000-03-27 | Merck & Co Inc | Thiazolobenzenosulphonamides as beta3 agonists for treating diabetes and obesity |
| BR0009486B1 (pt) * | 1999-03-29 | 2011-03-09 | composto que compreende uma amida, composição farmacêutica que compreende esse composto, seu uso e processo para a preparação do mesmo. |
-
2001
- 2001-08-08 US US09/924,247 patent/US6369232B1/en not_active Expired - Fee Related
- 2001-08-09 AU AU8399801A patent/AU8399801A/xx active Pending
- 2001-08-09 ES ES01962926T patent/ES2243541T3/es not_active Expired - Lifetime
- 2001-08-09 AU AU2001283998A patent/AU2001283998B2/en not_active Ceased
- 2001-08-09 MX MXPA03001275A patent/MXPA03001275A/es active IP Right Grant
- 2001-08-09 DK DK01962926T patent/DK1311504T3/da active
- 2001-08-09 WO PCT/EP2001/009207 patent/WO2002014312A1/en not_active Ceased
- 2001-08-09 JP JP2002519452A patent/JP3961948B2/ja not_active Expired - Fee Related
- 2001-08-09 CN CNB018163475A patent/CN1209362C/zh not_active Expired - Fee Related
- 2001-08-09 KR KR10-2003-7002231A patent/KR100518061B1/ko not_active Expired - Fee Related
- 2001-08-09 BR BR0113312-8A patent/BR0113312A/pt not_active IP Right Cessation
- 2001-08-09 DE DE60111540T patent/DE60111540T2/de not_active Expired - Lifetime
- 2001-08-09 EP EP01962926A patent/EP1311504B1/en not_active Expired - Lifetime
- 2001-08-09 PT PT01962926T patent/PT1311504E/pt unknown
- 2001-08-09 CA CA002419416A patent/CA2419416C/en not_active Expired - Fee Related
- 2001-08-09 AT AT01962926T patent/ATE297921T1/de not_active IP Right Cessation
- 2001-08-14 AR ARP010103886A patent/AR031718A1/es active IP Right Grant
- 2001-08-14 UY UY26885A patent/UY26885A1/es not_active Application Discontinuation
- 2001-08-14 PA PA20018525201A patent/PA8525201A1/es unknown
- 2001-08-15 PE PE2001000814A patent/PE20020386A1/es not_active Application Discontinuation
- 2001-10-11 US US09/975,713 patent/US6388088B1/en not_active Expired - Fee Related
-
2002
- 2002-01-16 US US10/050,508 patent/US6441180B1/en not_active Expired - Fee Related
-
2003
- 2003-01-31 ZA ZA200300904A patent/ZA200300904B/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101918363B (zh) * | 2008-01-18 | 2012-09-05 | 安斯泰来制药株式会社 | 苯乙酰胺衍生物 |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2419416C (en) | 2009-10-13 |
| UY26885A1 (es) | 2002-02-28 |
| WO2002014312A1 (en) | 2002-02-21 |
| US20020065275A1 (en) | 2002-05-30 |
| US20020035266A1 (en) | 2002-03-21 |
| KR100518061B1 (ko) | 2005-09-28 |
| AU8399801A (en) | 2002-02-25 |
| BR0113312A (pt) | 2003-07-01 |
| ES2243541T3 (es) | 2005-12-01 |
| EP1311504A1 (en) | 2003-05-21 |
| EP1311504B1 (en) | 2005-06-15 |
| CA2419416A1 (en) | 2002-02-21 |
| MXPA03001275A (es) | 2003-06-30 |
| US6388088B1 (en) | 2002-05-14 |
| US20020035267A1 (en) | 2002-03-21 |
| PE20020386A1 (es) | 2002-05-13 |
| ATE297921T1 (de) | 2005-07-15 |
| JP2004506632A (ja) | 2004-03-04 |
| ZA200300904B (en) | 2004-04-30 |
| CN1209362C (zh) | 2005-07-06 |
| DE60111540T2 (de) | 2006-03-16 |
| DE60111540D1 (de) | 2005-07-21 |
| PA8525201A1 (es) | 2002-07-30 |
| PT1311504E (pt) | 2005-10-31 |
| AU2001283998B2 (en) | 2005-10-20 |
| AR031718A1 (es) | 2003-10-01 |
| US6441180B1 (en) | 2002-08-27 |
| DK1311504T3 (da) | 2005-10-17 |
| KR20030022408A (ko) | 2003-03-15 |
| US6369232B1 (en) | 2002-04-09 |
| CN1466584A (zh) | 2004-01-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP3961948B2 (ja) | テトラゾリル−フェニルアセトアミドであるグルコキナーゼ活性化物質 | |
| AU2001283998A1 (en) | Tetrazolyl-phenyl acetamide glucokinase activators | |
| JP3824936B2 (ja) | ｔｒａｎｓオレフィン系グルコキナーゼアクチベーター | |
| 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 | |
| JP4138478B2 (ja) | アルファ−アシル及びアルファ−ヘテロ原子置換ベンゼンアセトアミドのグルコキナーゼアクチベーター | |
| JP4091600B2 (ja) | 置換フェニルアセトアミド及びグルコキナーゼ活性化物質としてのその使用 | |
| KR100545431B1 (ko) | 축합된 이종방향족 글루코키나제 활성화제 | |
| MXPA02010745A (es) | Activadores de glucocinasa heteroaromaticos de alquinil-fenilo. | |
| JP2002540196A (ja) | グルコキナーゼ活性化物質 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20070123 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20070406 |
|
| 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: 20070515 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20070517 |
|
| R150 | Certificate of patent or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20110525 Year of fee payment: 4 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20120525 Year of fee payment: 5 |
|
| LAPS | Cancellation because of no payment of annual fees |