JP5450108B2 - グルコキナーゼ活性化剤としての２−アミノピリジン類似体 - Google Patents
グルコキナーゼ活性化剤としての２−アミノピリジン類似体 Download PDFInfo
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- JP5450108B2 JP5450108B2 JP2009554721A JP2009554721A JP5450108B2 JP 5450108 B2 JP5450108 B2 JP 5450108B2 JP 2009554721 A JP2009554721 A JP 2009554721A JP 2009554721 A JP2009554721 A JP 2009554721A JP 5450108 B2 JP5450108 B2 JP 5450108B2
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- Prior art keywords
- mmol
- pyridin
- alkyl
- ylamino
- formula
- Prior art date
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- 108010021582 Glucokinase Proteins 0.000 title description 27
- 150000003930 2-aminopyridines Chemical class 0.000 title description 13
- 239000012190 activator Substances 0.000 title description 2
- 102000030595 Glucokinase Human genes 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 313
- 125000000217 alkyl group Chemical group 0.000 description 212
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 156
- 238000006243 chemical reaction Methods 0.000 description 156
- -1 Aminothiazolyl Chemical group 0.000 description 147
- 239000000460 chlorine Substances 0.000 description 139
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 126
- 238000000034 method Methods 0.000 description 110
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 99
- 239000000243 solution Substances 0.000 description 88
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 76
- 239000007787 solid Substances 0.000 description 74
- 235000019439 ethyl acetate Nutrition 0.000 description 73
- 239000002585 base Substances 0.000 description 69
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 65
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 60
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 58
- 229910052794 bromium Inorganic materials 0.000 description 58
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 58
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 57
- 239000000203 mixture Substances 0.000 description 56
- 229910052801 chlorine Inorganic materials 0.000 description 52
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 50
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 45
- 238000002360 preparation method Methods 0.000 description 39
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 38
- 229920006395 saturated elastomer Polymers 0.000 description 38
- 229910052938 sodium sulfate Inorganic materials 0.000 description 38
- 235000011152 sodium sulphate Nutrition 0.000 description 38
- 239000012044 organic layer Substances 0.000 description 37
- 229910052731 fluorine Inorganic materials 0.000 description 35
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 35
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 35
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 34
- 229910052757 nitrogen Inorganic materials 0.000 description 34
- 125000004429 atom Chemical group 0.000 description 33
- 125000003118 aryl group Chemical group 0.000 description 31
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 31
- 238000001819 mass spectrum Methods 0.000 description 31
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- 125000004433 nitrogen atom Chemical group N* 0.000 description 30
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 29
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 28
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 27
- 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 27
- 102100029237 Hexokinase-4 Human genes 0.000 description 27
- 239000008103 glucose Substances 0.000 description 27
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 26
- 239000000741 silica gel Substances 0.000 description 26
- 229910002027 silica gel Inorganic materials 0.000 description 26
- 229910052739 hydrogen Inorganic materials 0.000 description 24
- 239000002904 solvent Substances 0.000 description 24
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 24
- 239000003054 catalyst Substances 0.000 description 21
- 229910000104 sodium hydride Inorganic materials 0.000 description 20
- 150000003512 tertiary amines Chemical class 0.000 description 20
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 19
- 238000003556 assay Methods 0.000 description 18
- 150000003839 salts Chemical class 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- 230000015572 biosynthetic process Effects 0.000 description 17
- 201000010099 disease Diseases 0.000 description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 17
- 229910052717 sulfur Inorganic materials 0.000 description 17
- 229910052740 iodine Inorganic materials 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 15
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 15
- 150000003840 hydrochlorides Chemical class 0.000 description 15
- 238000003756 stirring Methods 0.000 description 15
- 208000035475 disorder Diseases 0.000 description 14
- 239000000463 material Substances 0.000 description 14
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 description 13
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 13
- 239000000543 intermediate Substances 0.000 description 13
- 229910052751 metal Inorganic materials 0.000 description 13
- 239000002184 metal Substances 0.000 description 13
- 229910052760 oxygen Inorganic materials 0.000 description 13
- 239000000377 silicon dioxide Substances 0.000 description 13
- 239000012312 sodium hydride Substances 0.000 description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000013058 crude material Substances 0.000 description 12
- 230000000694 effects Effects 0.000 description 12
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- 239000011734 sodium Substances 0.000 description 11
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 10
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 10
- 238000003818 flash chromatography Methods 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical compound NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- 125000000753 cycloalkyl group Chemical group 0.000 description 9
- 239000001257 hydrogen Substances 0.000 description 9
- 230000001404 mediated effect Effects 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- 239000008280 blood Substances 0.000 description 8
- 210000004369 blood Anatomy 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- 206010012601 diabetes mellitus Diseases 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
- 125000000623 heterocyclic group Chemical class 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 8
- 229910052763 palladium Inorganic materials 0.000 description 8
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
- FFNVQNRYTPFDDP-UHFFFAOYSA-N 2-cyanopyridine Chemical compound N#CC1=CC=CC=N1 FFNVQNRYTPFDDP-UHFFFAOYSA-N 0.000 description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 7
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 7
- 229910000024 caesium carbonate Inorganic materials 0.000 description 7
- 125000005842 heteroatom Chemical group 0.000 description 7
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 7
- XXNRDNXIPHATNM-UHFFFAOYSA-N n-(3-phenoxy-5-pyridin-2-ylsulfanylpyridin-2-yl)-3-piperidin-4-yl-1,2,4-thiadiazol-5-amine Chemical compound C1CNCCC1C1=NSC(NC=2C(=CC(SC=3N=CC=CC=3)=CN=2)OC=2C=CC=CC=2)=N1 XXNRDNXIPHATNM-UHFFFAOYSA-N 0.000 description 7
- CEJAFGHCMUGZCO-UHFFFAOYSA-N n-[3-(2-methylpyridin-3-yl)oxy-5-pyridin-2-ylsulfanylpyridin-2-yl]-3-piperidin-4-yl-1,2,4-thiadiazol-5-amine Chemical compound CC1=NC=CC=C1OC1=CC(SC=2N=CC=CC=2)=CN=C1NC1=NC(C2CCNCC2)=NS1 CEJAFGHCMUGZCO-UHFFFAOYSA-N 0.000 description 7
- 239000002002 slurry Substances 0.000 description 7
- VJHTZTZXOKVQRN-UHFFFAOYSA-N 1,2,4-thiadiazol-5-amine Chemical compound NC1=NC=NS1 VJHTZTZXOKVQRN-UHFFFAOYSA-N 0.000 description 6
- AQSRRZGQRFFFGS-UHFFFAOYSA-N 2-methylpyridin-3-ol Chemical compound CC1=NC=CC=C1O AQSRRZGQRFFFGS-UHFFFAOYSA-N 0.000 description 6
- 206010006895 Cachexia Diseases 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 6
- 230000002159 abnormal effect Effects 0.000 description 6
- 150000003927 aminopyridines Chemical class 0.000 description 6
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 6
- 239000010949 copper Substances 0.000 description 6
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 6
- 150000004820 halides Chemical class 0.000 description 6
- 229910052736 halogen Inorganic materials 0.000 description 6
- 150000002367 halogens Chemical class 0.000 description 6
- 230000000069 prophylactic effect Effects 0.000 description 6
- 229940124597 therapeutic agent Drugs 0.000 description 6
- 150000003573 thiols Chemical class 0.000 description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 5
- RZKVGQCJNANFDR-UHFFFAOYSA-N 5-chloro-1,2,4-thiadiazole Chemical compound ClC1=NC=NS1 RZKVGQCJNANFDR-UHFFFAOYSA-N 0.000 description 5
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 5
- YIIMEMSDCNDGTB-UHFFFAOYSA-N Dimethylcarbamoyl chloride Chemical compound CN(C)C(Cl)=O YIIMEMSDCNDGTB-UHFFFAOYSA-N 0.000 description 5
- 208000002705 Glucose Intolerance Diseases 0.000 description 5
- 241000124008 Mammalia Species 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 5
- 230000004913 activation Effects 0.000 description 5
- 150000001408 amides Chemical class 0.000 description 5
- 125000002619 bicyclic group Chemical group 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 229910052802 copper Inorganic materials 0.000 description 5
- JFCHSQDLLFJHOA-UHFFFAOYSA-N n,n-dimethylsulfamoyl chloride Chemical compound CN(C)S(Cl)(=O)=O JFCHSQDLLFJHOA-UHFFFAOYSA-N 0.000 description 5
- 125000004430 oxygen atom Chemical group O* 0.000 description 5
- 239000008194 pharmaceutical composition Substances 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 5
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- GKKCIDNWFBPDBW-UHFFFAOYSA-M potassium cyanate Chemical compound [K]OC#N GKKCIDNWFBPDBW-UHFFFAOYSA-M 0.000 description 5
- 201000009104 prediabetes syndrome Diseases 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 125000004076 pyridyl group Chemical group 0.000 description 5
- 230000002441 reversible effect Effects 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- MVAXDKDOPWPFML-UHFFFAOYSA-N 2-(dimethylamino)acetyl chloride;hydrochloride Chemical compound [Cl-].C[NH+](C)CC(Cl)=O MVAXDKDOPWPFML-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical class CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 206010020772 Hypertension Diseases 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-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-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- BXOBQDOEBJELFC-UHFFFAOYSA-N acetaldehyde;dihydrochloride Chemical compound Cl.Cl.CC=O BXOBQDOEBJELFC-UHFFFAOYSA-N 0.000 description 4
- ZVDDJPSHRNMSKV-UHFFFAOYSA-N acetaldehyde;hydrochloride Chemical compound Cl.CC=O ZVDDJPSHRNMSKV-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 230000003213 activating effect Effects 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 230000008878 coupling Effects 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 239000012954 diazonium Substances 0.000 description 4
- 150000001989 diazonium salts Chemical class 0.000 description 4
- 208000037765 diseases and disorders Diseases 0.000 description 4
- 239000006260 foam Substances 0.000 description 4
- 229910052744 lithium Inorganic materials 0.000 description 4
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 4
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 4
- 208000011580 syndromic disease Diseases 0.000 description 4
- QZEXDYYNSSEBFH-UHFFFAOYSA-N tert-butyl 4-(c-chloro-n-methylsulfonyloxycarbonimidoyl)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(C(Cl)=NOS(C)(=O)=O)CC1 QZEXDYYNSSEBFH-UHFFFAOYSA-N 0.000 description 4
- 125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 description 4
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 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
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 3
- HTLRSUUOAWNAPT-UHFFFAOYSA-N 1-[4-[5-[[5-bromo-3-(2-methylpyridin-3-yl)oxypyridin-2-yl]amino]-1,2,4-thiadiazol-3-yl]piperidin-1-yl]ethanone Chemical compound C1CN(C(=O)C)CCC1C1=NSC(NC=2C(=CC(Br)=CN=2)OC=2C(=NC=CC=2)C)=N1 HTLRSUUOAWNAPT-UHFFFAOYSA-N 0.000 description 3
- YZUPZGFPHUVJKC-UHFFFAOYSA-N 1-bromo-2-methoxyethane Chemical compound COCCBr YZUPZGFPHUVJKC-UHFFFAOYSA-N 0.000 description 3
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 3
- ABNQGNFVSFKJGI-UHFFFAOYSA-N 2,3-dichloro-5-(trifluoromethyl)pyridine Chemical compound FC(F)(F)C1=CN=C(Cl)C(Cl)=C1 ABNQGNFVSFKJGI-UHFFFAOYSA-N 0.000 description 3
- DTLBKXRFWUERQN-UHFFFAOYSA-N 3,5-dibromopyrazin-2-amine Chemical compound NC1=NC=C(Br)N=C1Br DTLBKXRFWUERQN-UHFFFAOYSA-N 0.000 description 3
- XVRBDMYOTCHFFU-UHFFFAOYSA-N 3-phenoxy-5-pyridin-2-ylsulfanylpyridin-2-amine Chemical compound C1=C(OC=2C=CC=CC=2)C(N)=NC=C1SC1=CC=CC=N1 XVRBDMYOTCHFFU-UHFFFAOYSA-N 0.000 description 3
- ICZNWYWLGWYNFS-UHFFFAOYSA-N 5-bromo-3-(2-methylpyridin-3-yl)oxypyridine-2-carbonitrile Chemical compound CC1=NC=CC=C1OC1=CC(Br)=CN=C1C#N ICZNWYWLGWYNFS-UHFFFAOYSA-N 0.000 description 3
- OBVYONPVHIOJJZ-UHFFFAOYSA-N 5-bromo-3-nitropyridine-2-carbonitrile Chemical compound [O-][N+](=O)C1=CC(Br)=CN=C1C#N OBVYONPVHIOJJZ-UHFFFAOYSA-N 0.000 description 3
- MDOCAWSPADWUMV-UHFFFAOYSA-N 5-bromo-3-phenoxypyridin-2-amine Chemical compound NC1=NC=C(Br)C=C1OC1=CC=CC=C1 MDOCAWSPADWUMV-UHFFFAOYSA-N 0.000 description 3
- 125000006163 5-membered heteroaryl group Chemical group 0.000 description 3
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
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- C07D417/14—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 three or more hetero rings
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Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US91971907P | 2007-03-23 | 2007-03-23 | |
| PCT/US2007/007444 WO2007117381A2 (en) | 2006-03-24 | 2007-03-23 | 2 -aminopyridine analogs as glucokinase activators |
| US60/919,719 | 2007-03-23 | ||
| USPCT/US2007/007444 | 2007-03-23 | ||
| US97426007P | 2007-09-21 | 2007-09-21 | |
| US60/974,260 | 2007-09-21 | ||
| PCT/US2008/057543 WO2008118718A2 (en) | 2007-03-23 | 2008-03-19 | 2-aminopyridine analogs as glucokinase activators |
Publications (3)
| Publication Number | Publication Date |
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| JP2010527911A JP2010527911A (ja) | 2010-08-19 |
| JP2010527911A5 JP2010527911A5 (https=) | 2012-05-10 |
| JP5450108B2 true JP5450108B2 (ja) | 2014-03-26 |
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| CN (1) | CN101679405A (https=) |
| CA (1) | CA2681695A1 (https=) |
| TW (1) | TW200843765A (https=) |
| WO (1) | WO2008118718A2 (https=) |
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| WO2008091770A1 (en) * | 2007-01-24 | 2008-07-31 | Array Biopharma Inc. | 2-aminopyridine derivatives as glucokinase activators |
| EP2573087A1 (en) | 2007-09-21 | 2013-03-27 | Array Biopharma, Inc. | Pyridin-2-yl-amino-1,2,4-thiadiazole derivatives as glucokinase activators for the treatment of diabetes mellitus |
| BRPI0818658A2 (pt) | 2007-10-09 | 2015-04-14 | Merck Patent Ges Mit Beschränkter Haftung | Derivados de piridina úteis como ativadores de glicoquinase |
| CN101970432B (zh) * | 2008-01-25 | 2014-05-28 | 杜邦公司 | 杀真菌杂环化合物 |
| AR077821A1 (es) * | 2009-08-11 | 2011-09-28 | Sanofi Aventis Us Llc | Procedimiento para preparar hidrocloruro de 4-metil-3-tienilamina |
| WO2011107494A1 (de) | 2010-03-03 | 2011-09-09 | Sanofi | Neue aromatische glykosidderivate, diese verbindungen enthaltende arzneimittel und deren verwendung |
| CN102959076B (zh) | 2010-03-31 | 2015-09-16 | 斯克里普斯研究所 | 重编程细胞 |
| EP2582709B1 (de) | 2010-06-18 | 2018-01-24 | Sanofi | Azolopyridin-3-on-derivate als inhibitoren von lipasen und phospholipasen |
| US8530413B2 (en) | 2010-06-21 | 2013-09-10 | Sanofi | Heterocyclically substituted methoxyphenyl derivatives with an oxo group, processes for preparation thereof and use thereof as medicaments |
| TW201215387A (en) | 2010-07-05 | 2012-04-16 | Sanofi Aventis | Spirocyclically substituted 1,3-propane dioxide derivatives, processes for preparation thereof and use thereof as a medicament |
| TW201221505A (en) | 2010-07-05 | 2012-06-01 | Sanofi Sa | Aryloxyalkylene-substituted hydroxyphenylhexynoic acids, process for preparation thereof and use thereof as a medicament |
| TW201215388A (en) | 2010-07-05 | 2012-04-16 | Sanofi Sa | (2-aryloxyacetylamino)phenylpropionic acid derivatives, processes for preparation thereof and use thereof as medicaments |
| JPWO2012121314A1 (ja) | 2011-03-09 | 2014-07-17 | 第一三共株式会社 | ジピリジルアミン誘導体 |
| WO2013037390A1 (en) | 2011-09-12 | 2013-03-21 | Sanofi | 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
| WO2013045413A1 (en) | 2011-09-27 | 2013-04-04 | Sanofi | 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
| CA2877026A1 (en) | 2012-05-18 | 2013-11-21 | Amgen Inc. | Method for the preparation of thiadiazoles |
| ES2619708T3 (es) | 2013-03-13 | 2017-06-26 | VIIV Healthcare UK (No.5) Limited | Inhibidores de la replicación del virus de inmunodeficiencia humana |
| WO2014164467A1 (en) | 2013-03-13 | 2014-10-09 | Bristol-Myers Squibb Company | Inhibitors of human immunodeficiency virus replication |
| WO2015091645A1 (en) | 2013-12-18 | 2015-06-25 | Basf Se | Azole compounds carrying an imine-derived substituent |
| SG10202001065SA (en) | 2014-03-28 | 2020-04-29 | Azevan Pharmaceuticals Inc | Compositions and methods for treating neurodegenerative diseases |
| CN106349159B (zh) * | 2016-08-29 | 2019-03-22 | 山东省联合农药工业有限公司 | 一种3-氯-2-氰基-5-三氟甲基吡啶的制备方法 |
| CN107286087B (zh) * | 2017-04-16 | 2020-01-07 | 内蒙古佳瑞米精细化工有限公司 | 一种2-氰基-3-氯-5-三氟甲基吡啶的合成方法 |
| MX2020002762A (es) | 2017-09-15 | 2020-09-17 | Azevan Pharmaceuticals Inc | Composiciones y métodos para tratar una lesión cerebral. |
| SG11202003879RA (en) | 2017-10-30 | 2020-05-28 | Neuropore Therapies Inc | Substituted phenyl sulfonyl phenyl triazole thiones and uses thereof |
| WO2020051424A1 (en) | 2018-09-07 | 2020-03-12 | Pic Therapeutics | Eif4e inhibitors and uses thereof |
| EP4077276A1 (en) | 2019-12-19 | 2022-10-26 | Curia Spain S.A.U. | Process and intermediates for the preparation of upadacitinib |
| TW202146393A (zh) | 2020-03-03 | 2021-12-16 | 美商皮克醫療公司 | Eif4e抑制劑及其用途 |
| US12157732B2 (en) | 2021-08-25 | 2024-12-03 | PIC Therapeutics, Inc. | eIF4E inhibitors and uses thereof |
| CA3229560A1 (en) | 2021-08-25 | 2023-03-02 | Christopher L. Vandeusen | Eif4e inhibitors and uses thereof |
| WO2023212237A1 (en) | 2022-04-27 | 2023-11-02 | Skyhawk Therapeutics, Inc. | Compositions useful for modulating splicing |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3703435A1 (de) * | 1987-02-05 | 1988-08-18 | Thomae Gmbh Dr K | Neue thiazole, diese verbindungen enthaltende arzneimittel und verfahren zu ihrer herstellung |
| US5260311A (en) * | 1989-02-22 | 1993-11-09 | Novo Nordisk A/S | Piperidine compounds and their use |
| NZ540791A (en) * | 2003-02-13 | 2009-09-25 | Banyu Pharma Co Ltd | Novel 2-pyridinecarboxamide derivatives |
| AR049418A1 (es) | 2004-02-27 | 2006-08-02 | Bayer Pharmaceuticals Corp | Derivados de heteroarilaminopirazol y composiciones farmaceuticas para el tratamiento de la diabetes. |
| US7687502B2 (en) | 2004-03-23 | 2010-03-30 | Banyu Pharmaceutical Co., Ltd. | Substituted quinazoline or pyridopyrimidine derivative |
| NZ567858A (en) * | 2005-11-01 | 2011-08-26 | Array Biopharma Inc | Pyridine compounds useful as Glucokinase activators |
| CN101437512A (zh) * | 2006-01-27 | 2009-05-20 | 阿雷生物药品公司 | 葡萄糖激酶活化剂 |
| RU2457207C2 (ru) * | 2006-03-24 | 2012-07-27 | Эррэй Биофарма Инк. | Активаторы глюкокиназы |
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- 2008-03-19 CA CA002681695A patent/CA2681695A1/en not_active Abandoned
- 2008-03-19 WO PCT/US2008/057543 patent/WO2008118718A2/en not_active Ceased
- 2008-03-19 JP JP2009554721A patent/JP5450108B2/ja not_active Expired - Fee Related
- 2008-03-19 CN CN200880017007A patent/CN101679405A/zh active Pending
- 2008-03-19 EP EP08732495A patent/EP2173745A2/en not_active Withdrawn
- 2008-03-19 US US12/532,374 patent/US8362037B2/en not_active Expired - Fee Related
- 2008-03-21 TW TW097110307A patent/TW200843765A/zh unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CA2681695A1 (en) | 2008-10-02 |
| US8362037B2 (en) | 2013-01-29 |
| JP2010527911A (ja) | 2010-08-19 |
| EP2173745A2 (en) | 2010-04-14 |
| CN101679405A (zh) | 2010-03-24 |
| US20100105659A1 (en) | 2010-04-29 |
| WO2008118718A2 (en) | 2008-10-02 |
| WO2008118718A3 (en) | 2008-11-13 |
| TW200843765A (en) | 2008-11-16 |
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