ES2378704T3 - Activadores de la glucocinasa - Google Patents
Activadores de la glucocinasa Download PDFInfo
- Publication number
- ES2378704T3 ES2378704T3 ES07716991T ES07716991T ES2378704T3 ES 2378704 T3 ES2378704 T3 ES 2378704T3 ES 07716991 T ES07716991 T ES 07716991T ES 07716991 T ES07716991 T ES 07716991T ES 2378704 T3 ES2378704 T3 ES 2378704T3
- Authority
- ES
- Spain
- Prior art keywords
- alkyl
- mmol
- saturated
- heteroaryl
- partially unsaturated
- 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.)
- Active
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- 102000030595 Glucokinase Human genes 0.000 title claims abstract description 52
- 108010021582 Glucokinase Proteins 0.000 title claims abstract description 52
- 239000012190 activator Substances 0.000 title description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 246
- 238000011282 treatment Methods 0.000 claims abstract description 48
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 43
- 230000003213 activating effect Effects 0.000 claims abstract description 9
- -1 2-tetrahydrofuranyl Chemical group 0.000 claims description 305
- 238000000034 method Methods 0.000 claims description 201
- 125000000623 heterocyclic group Chemical group 0.000 claims description 132
- 238000002360 preparation method Methods 0.000 claims description 132
- 229920006395 saturated elastomer Polymers 0.000 claims description 118
- 125000000217 alkyl group Chemical group 0.000 claims description 110
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 103
- 125000001072 heteroaryl group Chemical group 0.000 claims description 94
- 125000003342 alkenyl group Chemical group 0.000 claims description 81
- 125000000304 alkynyl group Chemical group 0.000 claims description 81
- 125000003118 aryl group Chemical group 0.000 claims description 79
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 71
- 229910052794 bromium Inorganic materials 0.000 claims description 49
- 239000000203 mixture Substances 0.000 claims description 48
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 47
- 229910052801 chlorine Inorganic materials 0.000 claims description 44
- 125000004429 atom Chemical group 0.000 claims description 30
- 229910052731 fluorine Inorganic materials 0.000 claims description 30
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 29
- 229910052717 sulfur Inorganic materials 0.000 claims description 26
- 239000003814 drug Substances 0.000 claims description 25
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 25
- 229910052757 nitrogen Inorganic materials 0.000 claims description 25
- 229910052740 iodine Inorganic materials 0.000 claims description 24
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 24
- 125000004043 oxo group Chemical group O=* 0.000 claims description 24
- 229910052760 oxygen Inorganic materials 0.000 claims description 22
- 125000002947 alkylene group Chemical group 0.000 claims description 20
- 201000010099 disease Diseases 0.000 claims description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 19
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 18
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 18
- 125000005842 heteroatom Chemical group 0.000 claims description 18
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 18
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 16
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 13
- 239000003054 catalyst Substances 0.000 claims description 13
- 125000004450 alkenylene group Chemical group 0.000 claims description 12
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 12
- 229940079593 drug Drugs 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- JCXJVPUVTGWSNB-UHFFFAOYSA-N nitrogen dioxide Inorganic materials O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims description 11
- 125000002619 bicyclic group Chemical group 0.000 claims description 9
- 125000002883 imidazolyl group Chemical group 0.000 claims description 8
- 125000002950 monocyclic group Chemical group 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
- 229910052751 metal Inorganic materials 0.000 claims description 7
- 239000002184 metal Substances 0.000 claims description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 7
- 125000004419 alkynylene group Chemical group 0.000 claims description 6
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 5
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 4
- 229910003827 NRaRb Inorganic materials 0.000 claims description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 4
- 238000002560 therapeutic procedure Methods 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- 125000004505 1,2,4-oxadiazol-5-yl group Chemical group O1N=CN=C1* 0.000 claims description 2
- 125000004509 1,3,4-oxadiazol-2-yl group Chemical group O1C(=NN=C1)* 0.000 claims description 2
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 claims description 2
- 108010081348 HRT1 protein Hairy Proteins 0.000 claims description 2
- 102100021881 Hairy/enhancer-of-split related with YRPW motif protein 1 Human genes 0.000 claims description 2
- VUWZPRWSIVNGKG-UHFFFAOYSA-N fluoromethane Chemical compound F[CH2] VUWZPRWSIVNGKG-UHFFFAOYSA-N 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 125000005493 quinolyl group Chemical group 0.000 claims description 2
- 229910052701 rubidium Inorganic materials 0.000 claims description 2
- 125000004588 thienopyridyl group Chemical group S1C(=CC2=C1C=CC=N2)* 0.000 claims description 2
- ZRHUHDUEXWHZMA-UHFFFAOYSA-N 1,4-dihydropyrazol-5-one Chemical compound O=C1CC=NN1 ZRHUHDUEXWHZMA-UHFFFAOYSA-N 0.000 claims 1
- LJKOFHPXVQFIQA-UHFFFAOYSA-N 1-[4-[2-[[4-(2,6-dichlorophenyl)sulfanylpyridin-2-yl]amino]-1,3-thiazol-4-yl]piperidin-1-yl]ethanone Chemical compound C1CN(C(=O)C)CCC1C1=CSC(NC=2N=CC=C(SC=3C(=CC=CC=3Cl)Cl)C=2)=N1 LJKOFHPXVQFIQA-UHFFFAOYSA-N 0.000 claims 1
- ZNEVZQJMMIYNCM-UHFFFAOYSA-N 1-[4-[2-[[4-(2,6-dimethylphenoxy)pyridin-2-yl]amino]-1,3-thiazol-4-yl]piperidin-1-yl]ethanone Chemical compound C1CN(C(=O)C)CCC1C1=CSC(NC=2N=CC=C(OC=3C(=CC=CC=3C)C)C=2)=N1 ZNEVZQJMMIYNCM-UHFFFAOYSA-N 0.000 claims 1
- UTIDUWCJLKFEMM-UHFFFAOYSA-N 1-[4-[2-[[4-(2-chloro-6-methylphenoxy)pyridin-2-yl]amino]-1,3-thiazol-4-yl]piperidin-1-yl]ethanone Chemical compound C1CN(C(=O)C)CCC1C1=CSC(NC=2N=CC=C(OC=3C(=CC=CC=3C)Cl)C=2)=N1 UTIDUWCJLKFEMM-UHFFFAOYSA-N 0.000 claims 1
- GBASZHHIBQYYME-UHFFFAOYSA-N 1-[4-[2-[[4-(2-chlorophenoxy)pyridin-2-yl]amino]-1,3-thiazol-4-yl]piperidin-1-yl]ethanone Chemical compound C1CN(C(=O)C)CCC1C1=CSC(NC=2N=CC=C(OC=3C(=CC=CC=3)Cl)C=2)=N1 GBASZHHIBQYYME-UHFFFAOYSA-N 0.000 claims 1
- GKGPSKQWWOBPCF-UHFFFAOYSA-N 3-[2-[[3-(1-acetylpiperidin-4-yl)-1,2,4-thiadiazol-5-yl]amino]-5-bromopyridin-4-yl]oxy-4-chloro-n-[2-(dimethylamino)ethyl]benzamide Chemical compound CN(C)CCNC(=O)C1=CC=C(Cl)C(OC=2C(=CN=C(NC=3SN=C(N=3)C3CCN(CC3)C(C)=O)C=2)Br)=C1 GKGPSKQWWOBPCF-UHFFFAOYSA-N 0.000 claims 1
- CJTXXGSSOGGONY-UHFFFAOYSA-N 3-[2-[[4-(1-acetylpiperidin-4-yl)-1,3-thiazol-2-yl]amino]pyridin-4-yl]oxypyridine-4-carbonitrile Chemical compound C1CN(C(=O)C)CCC1C1=CSC(NC=2N=CC=C(OC=3C(=CC=NC=3)C#N)C=2)=N1 CJTXXGSSOGGONY-UHFFFAOYSA-N 0.000 claims 1
- 206010011953 Decreased activity Diseases 0.000 claims 1
- 125000001589 carboacyl group Chemical group 0.000 claims 1
- 206010012601 diabetes mellitus Diseases 0.000 abstract description 35
- 208000035475 disorder Diseases 0.000 abstract description 24
- 230000001404 mediated effect Effects 0.000 abstract description 12
- 230000000694 effects Effects 0.000 abstract description 10
- 208000037765 diseases and disorders Diseases 0.000 abstract description 7
- 230000001771 impaired effect Effects 0.000 abstract description 6
- 206010056997 Impaired fasting glucose Diseases 0.000 abstract description 5
- 230000002950 deficient Effects 0.000 abstract description 5
- 208000002705 Glucose Intolerance Diseases 0.000 abstract description 4
- 230000006806 disease prevention Effects 0.000 abstract description 4
- 201000009104 prediabetes syndrome Diseases 0.000 abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 242
- 238000005160 1H NMR spectroscopy Methods 0.000 description 223
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 150
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 136
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 127
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 121
- 239000007787 solid Substances 0.000 description 121
- 239000011541 reaction mixture Substances 0.000 description 119
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 96
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 94
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 89
- 235000019439 ethyl acetate Nutrition 0.000 description 89
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 83
- 229910001868 water Inorganic materials 0.000 description 79
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 78
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 75
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 75
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 72
- 238000001819 mass spectrum Methods 0.000 description 68
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 66
- 238000006243 chemical reaction Methods 0.000 description 57
- 239000000243 solution Substances 0.000 description 56
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 48
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 47
- 229910000160 potassium phosphate Inorganic materials 0.000 description 47
- 235000011009 potassium phosphates Nutrition 0.000 description 47
- 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 45
- 239000008103 glucose Substances 0.000 description 44
- 239000000047 product Substances 0.000 description 42
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 41
- LIEPVGBDUYKPLC-UHFFFAOYSA-N 2-chloro-4-nitropyridine Chemical compound [O-][N+](=O)C1=CC=NC(Cl)=C1 LIEPVGBDUYKPLC-UHFFFAOYSA-N 0.000 description 39
- 229910000104 sodium hydride Inorganic materials 0.000 description 39
- 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 38
- 239000002480 mineral oil Substances 0.000 description 38
- 235000010446 mineral oil Nutrition 0.000 description 38
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 36
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 36
- 239000012312 sodium hydride Substances 0.000 description 36
- 239000012074 organic phase Substances 0.000 description 35
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 34
- 239000000460 chlorine Substances 0.000 description 33
- 239000003921 oil Substances 0.000 description 33
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[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.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 30
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 30
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 29
- OUQMXTJYCAJLGO-UHFFFAOYSA-N 4-methyl-1,3-thiazol-2-amine Chemical compound CC1=CSC(N)=N1 OUQMXTJYCAJLGO-UHFFFAOYSA-N 0.000 description 27
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 23
- HVHKUWRSDVJVIH-UHFFFAOYSA-N n-[5-bromo-4-(2,6-difluorophenoxy)pyridin-2-yl]-4-methyl-1,3-thiazol-2-amine Chemical compound CC1=CSC(NC=2N=CC(Br)=C(OC=3C(=CC=CC=3F)F)C=2)=N1 HVHKUWRSDVJVIH-UHFFFAOYSA-N 0.000 description 23
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- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 20
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 19
- 125000001424 substituent group Chemical group 0.000 description 19
- QMHIMXFNBOYPND-UHFFFAOYSA-N 4-methylthiazole Chemical compound CC1=CSC=N1 QMHIMXFNBOYPND-UHFFFAOYSA-N 0.000 description 18
- 238000004519 manufacturing process Methods 0.000 description 18
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 18
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 17
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- 238000010898 silica gel chromatography Methods 0.000 description 17
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 16
- 150000004820 halides Chemical class 0.000 description 16
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- 229910052943 magnesium sulfate Inorganic materials 0.000 description 14
- 235000019341 magnesium sulphate Nutrition 0.000 description 14
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 14
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N benzoic acid ethyl ester Natural products CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 13
- 239000008280 blood Substances 0.000 description 13
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- 125000004432 carbon atom Chemical group C* 0.000 description 13
- 239000013058 crude material Substances 0.000 description 13
- 239000012039 electrophile Substances 0.000 description 13
- 239000000463 material Substances 0.000 description 13
- 239000002904 solvent Substances 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 239000004215 Carbon black (E152) Substances 0.000 description 12
- 239000002585 base Substances 0.000 description 12
- 125000001309 chloro group Chemical group Cl* 0.000 description 12
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- 150000001412 amines Chemical class 0.000 description 11
- 125000001246 bromo group Chemical group Br* 0.000 description 11
- 239000000741 silica gel Substances 0.000 description 11
- 229910002027 silica gel Inorganic materials 0.000 description 11
- 229940124597 therapeutic agent Drugs 0.000 description 11
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 11
- 230000004913 activation Effects 0.000 description 10
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- 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
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- A61P3/00—Drugs for disorders of the metabolism
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- C07—ORGANIC CHEMISTRY
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- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Diabetes (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US76317306P | 2006-01-27 | 2006-01-27 | |
| US763173P | 2006-01-27 | ||
| PCT/US2007/001956 WO2007089512A1 (en) | 2006-01-27 | 2007-01-24 | Glucokinase activators |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2378704T3 true ES2378704T3 (es) | 2012-04-17 |
Family
ID=38109991
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES07716991T Active ES2378704T3 (es) | 2006-01-27 | 2007-01-24 | Activadores de la glucocinasa |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US8022222B2 (https=) |
| EP (1) | EP1986645B1 (https=) |
| JP (1) | JP5236499B2 (https=) |
| CN (1) | CN101437512A (https=) |
| AT (1) | ATE539748T1 (https=) |
| CA (1) | CA2637172A1 (https=) |
| ES (1) | ES2378704T3 (https=) |
| TW (1) | TW200740804A (https=) |
| WO (1) | WO2007089512A1 (https=) |
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| WO2008091770A1 (en) * | 2007-01-24 | 2008-07-31 | Array Biopharma Inc. | 2-aminopyridine derivatives as glucokinase activators |
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| WO2009022171A1 (en) * | 2007-08-13 | 2009-02-19 | Astrazeneca Ab | Pyridinyiioxy pyridines as alk5 inhibitors |
| WO2009022179A2 (en) * | 2007-08-14 | 2009-02-19 | Astrazeneca Ab | Glucokinase activators in the treatment of osteoarthritis |
| EP2025674A1 (de) | 2007-08-15 | 2009-02-18 | sanofi-aventis | Substituierte Tetrahydronaphthaline, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel |
| AU2008305294B2 (en) * | 2007-09-21 | 2012-11-29 | Array Biopharma Inc. | Pyridin-2 -yl-amino-1, 2, 4 -thiadiazole derivatives as glucokinase activators for the treatment of diabetes mellitus |
| JP5567481B2 (ja) * | 2007-10-09 | 2014-08-06 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング | グルコキナーゼアクチベーターとして有用なピリジン誘導体 |
| JP5693239B2 (ja) | 2008-01-23 | 2015-04-01 | ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ | ４−ピリジノン化合物および癌についてのその使用 |
| US7741327B2 (en) | 2008-04-16 | 2010-06-22 | Hoffmann-La Roche Inc. | Pyrrolidinone glucokinase activators |
| MY159230A (en) | 2008-10-02 | 2016-12-30 | Respivert Ltd | P38 map kinase inhibitors |
| JPWO2010058846A1 (ja) * | 2008-11-21 | 2012-04-19 | アステラス製薬株式会社 | ４，６−ジアミノニコチンアミド化合物 |
| JP5670912B2 (ja) | 2008-12-11 | 2015-02-18 | レスピバート・リミテツド | ｐ３８ＭＡＰキナーゼ阻害剤 |
| GB0905955D0 (en) | 2009-04-06 | 2009-05-20 | Respivert Ltd | Novel compounds |
| GB0921731D0 (en) | 2009-12-11 | 2010-01-27 | Respivert Ltd | Theraputic uses |
| GB0921730D0 (en) | 2009-12-11 | 2010-01-27 | Respivert Ltd | Method of treatment |
| WO2011107494A1 (de) | 2010-03-03 | 2011-09-09 | Sanofi | Neue aromatische glykosidderivate, diese verbindungen enthaltende arzneimittel und deren verwendung |
| CA2800498C (en) | 2010-03-31 | 2021-11-16 | The Scripps Research Institute | Reprogramming cells |
| GB201005589D0 (en) | 2010-04-01 | 2010-05-19 | Respivert Ltd | Novel compounds |
| EP2556068B1 (en) | 2010-04-08 | 2019-01-23 | Respivert Limited | P38 map kinase inhibitors |
| WO2011124923A2 (en) | 2010-04-08 | 2011-10-13 | Respivert Limited | Novel compounds |
| US8178689B2 (en) | 2010-06-17 | 2012-05-15 | Hoffman-La Roche Inc. | Tricyclic compounds |
| WO2011157827A1 (de) | 2010-06-18 | 2011-12-22 | 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 |
| 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 |
| 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 |
| KR20180099933A (ko) | 2010-11-19 | 2018-09-05 | 리간드 파마슈티칼스 인코포레이티드 | 복소환 아민 및 이의 용도 |
| US8871758B2 (en) | 2011-03-08 | 2014-10-28 | Sanofi | Tetrasubstituted oxathiazine derivatives, method for producing them, their use as medicine and drug containing said derivatives and the use thereof |
| US8828995B2 (en) | 2011-03-08 | 2014-09-09 | Sanofi | Branched oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof |
| EP2683699B1 (de) | 2011-03-08 | 2015-06-24 | Sanofi | Di- und trisubstituierte oxathiazinderivate, verfahren zu deren herstellung, ihre verwendung als medikament sowie sie enthaltendes arzneimittel und deren verwendung |
| EP2683705B1 (de) | 2011-03-08 | 2015-04-22 | Sanofi | Di- und trisubstituierte oxathiazinderivate, verfahren zu deren herstellung, ihre verwendung als medikament sowie sie enthaltendes arzneimittel und deren verwendung |
| WO2012120052A1 (de) | 2011-03-08 | 2012-09-13 | Sanofi | Mit carbozyklen oder heterozyklen substituierte oxathiazinderivate, verfahren zu deren herstellung, diese verbindungen enthaltende arzneimittel und deren verwendung |
| 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 |
| CN102786517B (zh) * | 2011-05-18 | 2017-06-06 | 中国医学科学院药物研究所 | Gk和ppar双重激动活性的嘧啶噻唑胺类衍生物 |
| JP5748210B2 (ja) * | 2011-05-26 | 2015-07-15 | 日本化薬株式会社 | 複素環化合物の製造方法 |
| KR20180084153A (ko) * | 2011-06-10 | 2018-07-24 | 메르크 파텐트 게엠베하 | Btk 억제 활성을 갖는 피리미딘 및 피리딘 화합물의 조성물 및 제조방법 |
| US9133174B2 (en) | 2011-09-05 | 2015-09-15 | Chugai Seiyaku Kabushiki Kaisha | Method for producing coumarin derivative |
| 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 |
| EP2760862B1 (en) | 2011-09-27 | 2015-10-21 | Sanofi | 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
| WO2013086397A1 (en) * | 2011-12-08 | 2013-06-13 | Array Biopharma Inc. | Urea compounds as gka activators |
| WO2013173672A1 (en) | 2012-05-18 | 2013-11-21 | Array Biopharma Inc. | Method for the preparation of thiadiazoles |
| CN104781251B (zh) * | 2012-11-08 | 2016-12-14 | 百时美施贵宝公司 | 可作为激酶调节剂的经双环杂环取代的吡啶基化合物 |
| WO2014076484A1 (en) | 2012-11-16 | 2014-05-22 | Respivert Limited | Kinase inhibitors |
| WO2014159938A1 (en) * | 2013-03-13 | 2014-10-02 | The Broad Institute, Inc. | Substituted aminothiazoles for the treatment of tuberculosis |
| WO2016001341A1 (en) * | 2014-07-03 | 2016-01-07 | F. Hoffmann-La Roche Ag | Sulfonylaminopyridine compounds, compositions and methods of use |
| CN106749002A (zh) * | 2015-02-12 | 2017-05-31 | 佛山市赛维斯医药科技有限公司 | 一种含硝基喹啉结构的葡萄糖激酶活化剂及其用途 |
| EP3259256B1 (en) * | 2015-02-17 | 2022-03-09 | Beijing Erai Therapeutics Co., Ltd. | Compounds and methods for inducing browning of white adipose tissue |
| US10807983B2 (en) | 2015-03-16 | 2020-10-20 | Ligand Pharmaceuticals, Inc. | Imidazo-fused heterocycles and uses thereof |
| AU2016245434B2 (en) * | 2015-04-07 | 2020-10-29 | Ela Pharma Ltd | Compositions for treating and/or preventing cell or tissue necrosis specifically targeting Cathepsin C and/or CELA1 and/or CELA3A and/or structurally related enzymes thereto |
| CN107848932B (zh) * | 2015-06-11 | 2025-09-02 | 解向群 | p62-ZZ化学抑制剂 |
| WO2017102091A1 (en) | 2015-12-18 | 2017-06-22 | Bayer Pharma Aktiengesellschaft | Heteroarylbenzimidazole compounds |
| WO2017207534A1 (en) | 2016-06-03 | 2017-12-07 | Bayer Pharma Aktiengesellschaft | Substituted heteroarylbenzimidazole compounds |
| EP3848370B1 (en) * | 2016-10-14 | 2025-05-07 | Takeda Pharmaceutical Company Limited | Tyk2 inhibitors and uses thereof |
| US12030875B2 (en) | 2018-09-07 | 2024-07-09 | PIC Therapeutics, Inc. | EIF4E inhibitors and uses thereof |
| EP3990445A4 (en) * | 2019-06-25 | 2023-07-05 | InventisBio Co., Ltd. | HETEROCYCLIC COMPOUNDS, METHODS FOR THEIR PREPARATION AND THEIR METHODS OF USE |
| CN110898049B (zh) * | 2019-11-29 | 2021-09-14 | 华中师范大学 | 二硫化合物在制备药物中的应用、fbp酶抑制剂及用于预防和/或治疗糖尿病的药剂 |
| AU2021230289A1 (en) | 2020-03-03 | 2022-09-29 | PIC Therapeutics, Inc. | eIF4E inhibitors and uses thereof |
| WO2022147694A1 (en) * | 2021-01-06 | 2022-07-14 | Beijing Erai Therapeutics Co., Ltd. | Aminoheteroaryl compounds and uses thereof |
| US12157732B2 (en) | 2021-08-25 | 2024-12-03 | PIC Therapeutics, Inc. | eIF4E inhibitors and uses thereof |
| JP2024534127A (ja) | 2021-08-25 | 2024-09-18 | ピク セラピューティクス， インコーポレイテッド | ｅＩＦ４Ｅ阻害剤及びその使用 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE60023926T2 (de) * | 1999-09-10 | 2006-07-20 | Merck & Co., Inc. | Tyrosin kinase inhibitoren |
| ATE316088T1 (de) | 2001-06-22 | 2006-02-15 | Merck & Co Inc | Tyrosin-kinase inhibitoren |
| WO2003078423A1 (en) * | 2002-03-15 | 2003-09-25 | Vertex Pharmaceuticals, Inc. | Compositions useful as inhibitors of protein kinases |
| US20040023981A1 (en) * | 2002-07-24 | 2004-02-05 | Yu Ren | Salt forms with tyrosine kinase activity |
| US20040023978A1 (en) * | 2002-07-24 | 2004-02-05 | Yu Ren | Active salt forms with tyrosine kinase activity |
| BR0314864A (pt) | 2002-10-03 | 2005-08-02 | Novartis Ag | Compostos orgânicos |
| CA2503715A1 (en) * | 2002-10-30 | 2004-05-21 | Merck & Co., Inc. | Kinase inhibitors |
| PL378117A1 (pl) | 2003-02-11 | 2006-03-06 | Prosidion Limited | Tricyklopodstawione związki amidowe |
| GB0328178D0 (en) * | 2003-12-05 | 2004-01-07 | Astrazeneca Ab | Compounds |
| CN1956982A (zh) * | 2004-05-21 | 2007-05-02 | 万有制药株式会社 | 具有氨基噻唑骨架的Cdk4、6选择性抑制剂 |
| RU2402544C2 (ru) | 2005-01-14 | 2010-10-27 | Си Джи Ай ФАРМАСЬЮТИКАЛЗ, ИНК. | 1,3-диарилзамещенные мочевины как модуляторы киназной активности |
| RU2368602C2 (ru) | 2005-01-26 | 2009-09-27 | Айрм Ллк | Соединения и композиции в качестве ингибиторов протеинкиназ |
| AU2006258101A1 (en) | 2005-06-09 | 2006-12-21 | Merck Sharp & Dohme Corp. | Inhibitors of checkpoint kinases |
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2007
- 2007-01-24 CA CA002637172A patent/CA2637172A1/en not_active Abandoned
- 2007-01-24 EP EP07716991A patent/EP1986645B1/en not_active Not-in-force
- 2007-01-24 US US12/161,366 patent/US8022222B2/en not_active Expired - Fee Related
- 2007-01-24 ES ES07716991T patent/ES2378704T3/es active Active
- 2007-01-24 WO PCT/US2007/001956 patent/WO2007089512A1/en not_active Ceased
- 2007-01-24 JP JP2008552395A patent/JP5236499B2/ja not_active Expired - Fee Related
- 2007-01-24 CN CNA2007800107261A patent/CN101437512A/zh active Pending
- 2007-01-24 AT AT07716991T patent/ATE539748T1/de active
- 2007-01-25 TW TW096102803A patent/TW200740804A/zh unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP1986645A1 (en) | 2008-11-05 |
| JP2009524670A (ja) | 2009-07-02 |
| EP1986645B1 (en) | 2012-01-04 |
| CA2637172A1 (en) | 2007-08-09 |
| US20090247526A1 (en) | 2009-10-01 |
| JP5236499B2 (ja) | 2013-07-17 |
| CN101437512A (zh) | 2009-05-20 |
| ATE539748T1 (de) | 2012-01-15 |
| US8022222B2 (en) | 2011-09-20 |
| WO2007089512A1 (en) | 2007-08-09 |
| TW200740804A (en) | 2007-11-01 |
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