CA2791947A1 - Derives de 1h-pyrazolo[4,3-c]isoquinoleines, leur preparation et leur application en therapeutique - Google Patents
Derives de 1h-pyrazolo[4,3-c]isoquinoleines, leur preparation et leur application en therapeutique Download PDFInfo
- Publication number
- CA2791947A1 CA2791947A1 CA2791947A CA2791947A CA2791947A1 CA 2791947 A1 CA2791947 A1 CA 2791947A1 CA 2791947 A CA2791947 A CA 2791947A CA 2791947 A CA2791947 A CA 2791947A CA 2791947 A1 CA2791947 A1 CA 2791947A1
- Authority
- CA
- Canada
- Prior art keywords
- pyrazolo
- difluorophenyl
- group
- amino
- piperidin
- 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.)
- Abandoned
Links
- 238000002360 preparation method Methods 0.000 title claims description 12
- 125000002183 isoquinolinyl group Chemical class C1(=NC=CC2=CC=CC=C12)* 0.000 title 1
- 230000001225 therapeutic effect Effects 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 57
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 30
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 23
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 14
- 239000001257 hydrogen Substances 0.000 claims abstract description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 9
- 125000005843 halogen group Chemical group 0.000 claims abstract description 6
- 125000003709 fluoroalkyl group Chemical group 0.000 claims abstract description 4
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims abstract description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 3
- -1 2,6-difluoro-phenyl Chemical group 0.000 claims description 97
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 45
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 38
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 21
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 18
- 125000006239 protecting group Chemical group 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 13
- SEDZOYHHAIAQIW-UHFFFAOYSA-N trimethylsilyl azide Chemical compound C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 claims description 9
- 125000004429 atom Chemical group 0.000 claims description 8
- 230000008878 coupling Effects 0.000 claims description 8
- 238000010168 coupling process Methods 0.000 claims description 8
- 238000005859 coupling reaction Methods 0.000 claims description 8
- 239000011541 reaction mixture Substances 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 150000001412 amines Chemical class 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000004551 isoquinolin-3-yl group Chemical group C1=NC(=CC2=CC=CC=C12)* 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 6
- GUQZRLYVVFIRHR-UHFFFAOYSA-N 5-(2,6-difluorophenyl)-3-[(1-methylsulfonylpiperidin-4-yl)amino]-1h-pyrazolo[4,3-c]isoquinoline-7-carbonitrile Chemical compound C1CN(S(=O)(=O)C)CCC1NC1=NNC(C2=CC=C(C=C22)C#N)=C1N=C2C1=C(F)C=CC=C1F GUQZRLYVVFIRHR-UHFFFAOYSA-N 0.000 claims description 5
- 125000006125 ethylsulfonyl group Chemical group 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- IJBGDEFHSQBFSG-UHFFFAOYSA-N 3-[(1-cyclopropylsulfonylpiperidin-4-yl)amino]-5-(2,6-difluorophenyl)-1h-pyrazolo[4,3-c]isoquinoline-7-carbonitrile Chemical compound FC1=CC=CC(F)=C1C(C1=CC(=CC=C11)C#N)=NC2=C1NN=C2NC1CCN(S(=O)(=O)C2CC2)CC1 IJBGDEFHSQBFSG-UHFFFAOYSA-N 0.000 claims description 4
- 229910052763 palladium Inorganic materials 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- YJDSZYYXQHESAL-UHFFFAOYSA-N 4-[[5-(2,6-difluorophenyl)-7-(hydroxymethyl)-1h-pyrazolo[4,3-c]isoquinolin-3-yl]amino]piperidine-1-sulfonamide Chemical compound C1CN(S(=O)(=O)N)CCC1NC1=NNC(C2=CC=C(CO)C=C22)=C1N=C2C1=C(F)C=CC=C1F YJDSZYYXQHESAL-UHFFFAOYSA-N 0.000 claims description 3
- KGRMVLZLUGWXOJ-UHFFFAOYSA-N 5-(2,6-difluorophenyl)-3-[(1-ethylsulfonylpiperidin-4-yl)amino]-1h-pyrazolo[4,3-c]isoquinoline-7-carbaldehyde Chemical compound C1CN(S(=O)(=O)CC)CCC1NC1=NNC(C2=CC=C(C=O)C=C22)=C1N=C2C1=C(F)C=CC=C1F KGRMVLZLUGWXOJ-UHFFFAOYSA-N 0.000 claims description 3
- HDPQMXVWWMHIPF-UHFFFAOYSA-N 5-(2,6-difluorophenyl)-3-[(1-ethylsulfonylpiperidin-4-yl)amino]-1h-pyrazolo[4,3-c]isoquinoline-7-carboxamide Chemical compound C1CN(S(=O)(=O)CC)CCC1NC1=NNC(C2=CC=C(C=C22)C(N)=O)=C1N=C2C1=C(F)C=CC=C1F HDPQMXVWWMHIPF-UHFFFAOYSA-N 0.000 claims description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 3
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 3
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 claims description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- FLKRMXAWABTWSH-UHFFFAOYSA-N piperidine-1-sulfonamide Chemical compound NS(=O)(=O)N1CCCCC1 FLKRMXAWABTWSH-UHFFFAOYSA-N 0.000 claims description 3
- NQJCBCPYVOOEHU-UHFFFAOYSA-N 3-[(1-cyclopropylsulfonylpiperidin-4-yl)amino]-5-(2,6-difluorophenyl)-1h-pyrazolo[4,3-c]isoquinoline-7-carboxamide Chemical compound C1=2N=C(C=3C(=CC=CC=3F)F)C3=CC(C(=O)N)=CC=C3C=2NN=C1NC(CC1)CCN1S(=O)(=O)C1CC1 NQJCBCPYVOOEHU-UHFFFAOYSA-N 0.000 claims description 2
- KEVXLLCQBCBCJN-UHFFFAOYSA-N 4-[[7-cyano-5-(2,6-difluorophenyl)-1h-pyrazolo[4,3-c]isoquinolin-3-yl]amino]piperidine-1-sulfonamide Chemical compound C1CN(S(=O)(=O)N)CCC1NC1=NNC(C2=CC=C(C=C22)C#N)=C1N=C2C1=C(F)C=CC=C1F KEVXLLCQBCBCJN-UHFFFAOYSA-N 0.000 claims description 2
- KAMIUDBIEZUGRD-UHFFFAOYSA-N 5-(2,6-difluorophenyl)-3-[(1-ethylsulfonylpiperidin-4-yl)amino]-1h-pyrazolo[4,3-c]isoquinoline-7-carbonitrile Chemical compound C1CN(S(=O)(=O)CC)CCC1NC1=NNC(C2=CC=C(C=C22)C#N)=C1N=C2C1=C(F)C=CC=C1F KAMIUDBIEZUGRD-UHFFFAOYSA-N 0.000 claims description 2
- HVIJNAFSDFOABE-UHFFFAOYSA-N 5-(2,6-difluorophenyl)-3-[(1-methylsulfonylpiperidin-4-yl)amino]-1h-pyrazolo[4,3-c]isoquinoline-7-carbaldehyde Chemical compound C1CN(S(=O)(=O)C)CCC1NC1=NNC(C2=CC=C(C=O)C=C22)=C1N=C2C1=C(F)C=CC=C1F HVIJNAFSDFOABE-UHFFFAOYSA-N 0.000 claims description 2
- DGCKNPDFYYUIFV-UHFFFAOYSA-N 5-(2,6-difluorophenyl)-3-[(1-methylsulfonylpiperidin-4-yl)amino]-1h-pyrazolo[4,3-c]isoquinoline-7-carbothioamide Chemical compound C1CN(S(=O)(=O)C)CCC1NC1=NNC(C2=CC=C(C=C22)C(N)=S)=C1N=C2C1=C(F)C=CC=C1F DGCKNPDFYYUIFV-UHFFFAOYSA-N 0.000 claims description 2
- NTUDVKOTCJWOGK-UHFFFAOYSA-N 5-(2,6-difluorophenyl)-3-[(1-methylsulfonylpiperidin-4-yl)amino]-1h-pyrazolo[4,3-c]isoquinoline-7-carboxamide Chemical compound C1CN(S(=O)(=O)C)CCC1NC1=NNC(C2=CC=C(C=C22)C(N)=O)=C1N=C2C1=C(F)C=CC=C1F NTUDVKOTCJWOGK-UHFFFAOYSA-N 0.000 claims description 2
- DSJVZAMEIDDNFJ-UHFFFAOYSA-N 5-(2,6-difluorophenyl)-3-[[1-(trifluoromethylsulfonyl)piperidin-4-yl]amino]-1h-pyrazolo[4,3-c]isoquinoline-7-carboxamide Chemical compound C1=2N=C(C=3C(=CC=CC=3F)F)C3=CC(C(=O)N)=CC=C3C=2NN=C1NC1CCN(S(=O)(=O)C(F)(F)F)CC1 DSJVZAMEIDDNFJ-UHFFFAOYSA-N 0.000 claims description 2
- JEQFXIVSJGPTBW-UHFFFAOYSA-N 5-(2,6-difluorophenyl)-7-ethenyl-n-(1-methylsulfonylpiperidin-4-yl)-1h-pyrazolo[4,3-c]isoquinolin-3-amine Chemical compound C1CN(S(=O)(=O)C)CCC1NC1=NNC(C2=CC=C(C=C)C=C22)=C1N=C2C1=C(F)C=CC=C1F JEQFXIVSJGPTBW-UHFFFAOYSA-N 0.000 claims description 2
- POXMAXYPOXUVSC-UHFFFAOYSA-N 5-(2,6-difluorophenyl)-7-ethynyl-n-(1-methylsulfonylpiperidin-4-yl)-1h-pyrazolo[4,3-c]isoquinolin-3-amine Chemical compound C1CN(S(=O)(=O)C)CCC1NC1=NNC(C2=CC=C(C=C22)C#C)=C1N=C2C1=C(F)C=CC=C1F POXMAXYPOXUVSC-UHFFFAOYSA-N 0.000 claims description 2
- ANAJNNLDOVJWNJ-UHFFFAOYSA-N 5-(2,6-difluorophenyl)-N'-hydroxy-3-[(1-methylsulfonylpiperidin-4-yl)amino]-1H-pyrazolo[4,3-c]isoquinoline-7-carboximidamide Chemical compound C1CN(S(=O)(=O)C)CCC1NC1=NNC(C2=CC=C(C=C22)C(=N)NO)=C1N=C2C1=C(F)C=CC=C1F ANAJNNLDOVJWNJ-UHFFFAOYSA-N 0.000 claims description 2
- STCPUAMYUVSVEY-UHFFFAOYSA-N 5-(2,6-difluorophenyl)-n-(1-methylsulfonylpiperidin-4-yl)-1h-pyrazolo[4,3-c]isoquinolin-3-amine Chemical compound C1CN(S(=O)(=O)C)CCC1NC1=NNC(C2=CC=CC=C22)=C1N=C2C1=C(F)C=CC=C1F STCPUAMYUVSVEY-UHFFFAOYSA-N 0.000 claims description 2
- QPDRVSSQFCIGML-UHFFFAOYSA-N 5-(2,6-difluorophenyl)-n-(1-methylsulfonylpiperidin-4-yl)-7-(1h-pyrazol-4-yl)-1h-pyrazolo[4,3-c]isoquinolin-3-amine Chemical compound C1CN(S(=O)(=O)C)CCC1NC1=NNC(C2=CC=C(C=C22)C3=CNN=C3)=C1N=C2C1=C(F)C=CC=C1F QPDRVSSQFCIGML-UHFFFAOYSA-N 0.000 claims description 2
- CTNSZZYEBNHWAK-UHFFFAOYSA-N 5-(2,6-difluorophenyl)-n-(1-methylsulfonylpiperidin-4-yl)-7-(2h-triazol-4-yl)-1h-pyrazolo[4,3-c]isoquinolin-3-amine Chemical compound C1CN(S(=O)(=O)C)CCC1NC1=NNC(C2=CC=C(C=C22)C3=NNN=C3)=C1N=C2C1=C(F)C=CC=C1F CTNSZZYEBNHWAK-UHFFFAOYSA-N 0.000 claims description 2
- STJJDNLONRBDPP-UHFFFAOYSA-N N-[[5-(2,6-difluorophenyl)-3-[(1-ethylsulfonylpiperidin-4-yl)amino]-1H-pyrazolo[4,3-c]isoquinolin-7-yl]methylidene]hydroxylamine Chemical compound C1CN(S(=O)(=O)CC)CCC1NC1=NNC(C2=CC=C(C=NO)C=C22)=C1N=C2C1=C(F)C=CC=C1F STJJDNLONRBDPP-UHFFFAOYSA-N 0.000 claims description 2
- 206010028980 Neoplasm Diseases 0.000 claims description 2
- 239000002246 antineoplastic agent Substances 0.000 claims description 2
- 238000006352 cycloaddition reaction Methods 0.000 claims description 2
- 229940126601 medicinal product Drugs 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 230000001131 transforming effect Effects 0.000 claims 2
- YOUTXQDWEMQOAE-UHFFFAOYSA-N 5-(2,6-difluorophenyl)-3-[(1-sulfamoylpiperidin-4-yl)amino]-1h-pyrazolo[4,3-c]isoquinoline-7-carboxamide Chemical compound C=12N=C(C=3C(=CC=CC=3F)F)C3=CC(C(=O)N)=CC=C3C2=NNC=1NC1CCN(S(N)(=O)=O)CC1 YOUTXQDWEMQOAE-UHFFFAOYSA-N 0.000 claims 1
- CFVDITVGKOGSEN-UHFFFAOYSA-N 5-(2,6-difluorophenyl)-7-fluoro-n-(1-methylsulfonylpiperidin-4-yl)-1h-pyrazolo[4,3-c]isoquinolin-3-amine Chemical compound C1CN(S(=O)(=O)C)CCC1NC1=NNC(C2=CC=C(F)C=C22)=C1N=C2C1=C(F)C=CC=C1F CFVDITVGKOGSEN-UHFFFAOYSA-N 0.000 claims 1
- HEUWEXGAILEABO-UHFFFAOYSA-N N-[[5-(2,6-difluorophenyl)-3-[(1-methylsulfonylpiperidin-4-yl)amino]-1H-pyrazolo[4,3-c]isoquinolin-7-yl]methylidene]hydroxylamine Chemical compound C1CN(S(=O)(=O)C)CCC1NC1=NNC(C2=CC=C(C=NO)C=C22)=C1N=C2C1=C(F)C=CC=C1F HEUWEXGAILEABO-UHFFFAOYSA-N 0.000 claims 1
- 201000011510 cancer Diseases 0.000 claims 1
- 230000003301 hydrolyzing effect Effects 0.000 claims 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 1
- 101000977048 Streptomyces cinnamonensis Uncharacterized protein in mutB 3'region Proteins 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 description 218
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 165
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 148
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 138
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 128
- 239000007787 solid Substances 0.000 description 126
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 109
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 84
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 76
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 74
- 229910052786 argon Inorganic materials 0.000 description 69
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 64
- 235000019341 magnesium sulphate Nutrition 0.000 description 64
- 239000000741 silica gel Substances 0.000 description 60
- 229910002027 silica gel Inorganic materials 0.000 description 60
- 238000003818 flash chromatography Methods 0.000 description 56
- 239000000243 solution Substances 0.000 description 53
- 238000001816 cooling Methods 0.000 description 48
- 238000003760 magnetic stirring Methods 0.000 description 44
- 239000011780 sodium chloride Substances 0.000 description 43
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 42
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 40
- 238000005160 1H NMR spectroscopy Methods 0.000 description 35
- 238000000105 evaporative light scattering detection Methods 0.000 description 35
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 34
- 238000001819 mass spectrum Methods 0.000 description 32
- 238000005481 NMR spectroscopy Methods 0.000 description 31
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 31
- 239000007864 aqueous solution Substances 0.000 description 31
- 229920006395 saturated elastomer Polymers 0.000 description 31
- 238000006243 chemical reaction Methods 0.000 description 27
- 238000010992 reflux Methods 0.000 description 26
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- 239000000284 extract Substances 0.000 description 24
- 239000012074 organic phase Substances 0.000 description 24
- 125000003821 2-(trimethylsilyl)ethoxymethyl group Chemical group [H]C([H])([H])[Si](C([H])([H])[H])(C([H])([H])[H])C([H])([H])C(OC([H])([H])[*])([H])[H] 0.000 description 22
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 22
- 239000012141 concentrate Substances 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- 239000012047 saturated solution Substances 0.000 description 19
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 17
- 230000005587 bubbling Effects 0.000 description 17
- 239000000047 product Substances 0.000 description 17
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 15
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 235000011114 ammonium hydroxide Nutrition 0.000 description 15
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 15
- 239000006071 cream Substances 0.000 description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- 239000008346 aqueous phase Substances 0.000 description 14
- 229910000024 caesium carbonate Inorganic materials 0.000 description 14
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 14
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 13
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 13
- 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 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 12
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 12
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- 239000000725 suspension Substances 0.000 description 10
- FLQSRSQNICPZIH-UHFFFAOYSA-N 1-methylsulfonylpiperidin-4-amine Chemical compound CS(=O)(=O)N1CCC(N)CC1 FLQSRSQNICPZIH-UHFFFAOYSA-N 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- 229910021529 ammonia Inorganic materials 0.000 description 9
- 229910052794 bromium Inorganic materials 0.000 description 9
- 239000002609 medium Substances 0.000 description 9
- 239000012429 reaction media Substances 0.000 description 9
- BPXKZEMBEZGUAH-UHFFFAOYSA-N 2-(chloromethoxy)ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCCl BPXKZEMBEZGUAH-UHFFFAOYSA-N 0.000 description 8
- AWJKWSNEKWBSAR-UHFFFAOYSA-N 3-bromo-5-(2,6-difluorophenyl)-1-(2-trimethylsilylethoxymethyl)pyrazolo[4,3-c]isoquinoline-7-carbonitrile Chemical compound C=12C=C(C#N)C=CC2=C2N(COCC[Si](C)(C)C)N=C(Br)C2=NC=1C1=C(F)C=CC=C1F AWJKWSNEKWBSAR-UHFFFAOYSA-N 0.000 description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 8
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 8
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 8
- 238000004587 chromatography analysis Methods 0.000 description 8
- 238000000034 method Methods 0.000 description 8
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- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000001345 alkine derivatives Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 1
- RROBIDXNTUAHFW-UHFFFAOYSA-N benzotriazol-1-yloxy-tris(dimethylamino)phosphanium Chemical compound C1=CC=C2N(O[P+](N(C)C)(N(C)C)N(C)C)N=NC2=C1 RROBIDXNTUAHFW-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- XJHCXCQVJFPJIK-UHFFFAOYSA-M cesium fluoride Substances [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 150000001879 copper Chemical class 0.000 description 1
- 238000007333 cyanation reaction Methods 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 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 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 229960005215 dichloroacetic acid Drugs 0.000 description 1
- IMDXZWRLUZPMDH-UHFFFAOYSA-N dichlorophenylphosphine Chemical compound ClP(Cl)C1=CC=CC=C1 IMDXZWRLUZPMDH-UHFFFAOYSA-N 0.000 description 1
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 1
- 125000004212 difluorophenyl group Chemical group 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- HDFXRQJQZBPDLF-UHFFFAOYSA-L disodium hydrogen carbonate Chemical compound [Na+].[Na+].OC([O-])=O.OC([O-])=O HDFXRQJQZBPDLF-UHFFFAOYSA-L 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 238000003682 fluorination reaction Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 150000003840 hydrochlorides Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- VYCKDIRCVDCQAE-UHFFFAOYSA-N isoquinolin-3-amine Chemical compound C1=CC=C2C=NC(N)=CC2=C1 VYCKDIRCVDCQAE-UHFFFAOYSA-N 0.000 description 1
- QYWRGRMDETYNJX-UHFFFAOYSA-N isoquinoline-7-carbothioamide Chemical compound C1=CN=CC2=CC(C(=S)N)=CC=C21 QYWRGRMDETYNJX-UHFFFAOYSA-N 0.000 description 1
- RFYKMRGOPAKUHD-UHFFFAOYSA-N isoquinoline-7-carboximidamide Chemical compound C1=CN=CC2=CC(C(=N)N)=CC=C21 RFYKMRGOPAKUHD-UHFFFAOYSA-N 0.000 description 1
- 150000002537 isoquinolines Chemical class 0.000 description 1
- UEGPKNKPLBYCNK-UHFFFAOYSA-L magnesium acetate Chemical compound [Mg+2].CC([O-])=O.CC([O-])=O UEGPKNKPLBYCNK-UHFFFAOYSA-L 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- NQJPKDOLQGDBOS-UHFFFAOYSA-N methyl 5-(2,6-difluorophenyl)-3-[(1-methylsulfonylpiperidin-4-yl)amino]-2-(2-trimethylsilylethoxymethyl)pyrazolo[4,3-c]isoquinoline-7-carboxylate Chemical compound C=12N=C(C=3C(=CC=CC=3F)F)C3=CC(C(=O)OC)=CC=C3C2=NN(COCC[Si](C)(C)C)C=1NC1CCN(S(C)(=O)=O)CC1 NQJPKDOLQGDBOS-UHFFFAOYSA-N 0.000 description 1
- IBSCADYIYSQTJC-UHFFFAOYSA-N methyl isoquinoline-7-carboxylate Chemical compound C1=CN=CC2=CC(C(=O)OC)=CC=C21 IBSCADYIYSQTJC-UHFFFAOYSA-N 0.000 description 1
- CLXPVBYKMMVMFB-UHFFFAOYSA-N n-[1-(2,6-difluorobenzoyl)-5-(4-fluorophenyl)pyrazol-4-yl]-2,6-difluorobenzamide Chemical compound C1=CC(F)=CC=C1C(N(N=C1)C(=O)C=2C(=CC=CC=2F)F)=C1NC(=O)C1=C(F)C=CC=C1F CLXPVBYKMMVMFB-UHFFFAOYSA-N 0.000 description 1
- PNQBYFZJSASWNL-UHFFFAOYSA-N n-[1-(2,6-difluorobenzoyl)-5-phenylpyrazol-4-yl]-2,6-difluorobenzamide Chemical compound FC1=CC=CC(F)=C1C(=O)NC1=C(C=2C=CC=CC=2)N(C(=O)C=2C(=CC=CC=2F)F)N=C1 PNQBYFZJSASWNL-UHFFFAOYSA-N 0.000 description 1
- WLAOAQMYBLONJR-UHFFFAOYSA-N n-piperidin-4-ylcyclopropanesulfonamide Chemical compound C1CC1S(=O)(=O)NC1CCNCC1 WLAOAQMYBLONJR-UHFFFAOYSA-N 0.000 description 1
- UXYJYTYMDZTSNI-UHFFFAOYSA-N n-piperidin-4-ylethanesulfonamide Chemical compound CCS(=O)(=O)NC1CCNCC1 UXYJYTYMDZTSNI-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 229910052762 osmium Inorganic materials 0.000 description 1
- SYQBFIAQOQZEGI-UHFFFAOYSA-N osmium atom Chemical compound [Os] SYQBFIAQOQZEGI-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 150000002923 oximes Chemical group 0.000 description 1
- 150000002940 palladium Chemical class 0.000 description 1
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 description 1
- 229940066842 petrolatum Drugs 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- IMACFCSSMIZSPP-UHFFFAOYSA-N phenacyl chloride Chemical compound ClCC(=O)C1=CC=CC=C1 IMACFCSSMIZSPP-UHFFFAOYSA-N 0.000 description 1
- YKDJGQHRXRYYRM-UHFFFAOYSA-N phenylphosphane;dihydrochloride Chemical compound Cl.Cl.PC1=CC=CC=C1 YKDJGQHRXRYYRM-UHFFFAOYSA-N 0.000 description 1
- RPGWZZNNEUHDAQ-UHFFFAOYSA-N phenylphosphine Chemical compound PC1=CC=CC=C1 RPGWZZNNEUHDAQ-UHFFFAOYSA-N 0.000 description 1
- LWMPFIOTEAXAGV-UHFFFAOYSA-N piperidin-1-amine Chemical compound NN1CCCCC1 LWMPFIOTEAXAGV-UHFFFAOYSA-N 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Natural products CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- LZRDHSFPLUWYAX-UHFFFAOYSA-N tert-butyl 4-aminopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(N)CC1 LZRDHSFPLUWYAX-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- CKXZPVPIDOJLLM-UHFFFAOYSA-N tert-butyl n-piperidin-4-ylcarbamate Chemical compound CC(C)(C)OC(=O)NC1CCNCC1 CKXZPVPIDOJLLM-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- GRGCWBWNLSTIEN-UHFFFAOYSA-N trifluoromethanesulfonyl chloride Chemical compound FC(F)(F)S(Cl)(=O)=O GRGCWBWNLSTIEN-UHFFFAOYSA-N 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical compound C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- 235000019798 tripotassium phosphate Nutrition 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000010930 yellow gold Substances 0.000 description 1
- 229910001097 yellow gold Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR09/01995 | 2009-04-24 | ||
| FR0901995A FR2944792B1 (fr) | 2009-04-24 | 2009-04-24 | Derives de 1h-pyrazolo[4,3-c]isoquinoleines, leur preparation et leur application en therapeutique |
| PCT/FR2010/050773 WO2010122272A1 (fr) | 2009-04-24 | 2010-04-22 | DERIVES DE 1-PYRAZOLO[4,3-c]ISOQUINOLEINES, LEUR PREPARATION ET LEUR APPLICATION EN THERAPEUTIQUE |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2791947A1 true CA2791947A1 (fr) | 2010-10-28 |
Family
ID=41259738
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2791947A Abandoned CA2791947A1 (fr) | 2009-04-24 | 2010-04-22 | Derives de 1h-pyrazolo[4,3-c]isoquinoleines, leur preparation et leur application en therapeutique |
Country Status (25)
| Country | Link |
|---|---|
| US (1) | US8461175B2 (enExample) |
| EP (1) | EP2421864B1 (enExample) |
| JP (1) | JP5722880B2 (enExample) |
| KR (1) | KR101675609B1 (enExample) |
| CN (1) | CN102459260B (enExample) |
| AR (1) | AR076393A1 (enExample) |
| AU (1) | AU2010240742B2 (enExample) |
| BR (1) | BRPI1013724A2 (enExample) |
| CA (1) | CA2791947A1 (enExample) |
| CY (1) | CY1115678T1 (enExample) |
| DK (1) | DK2421864T3 (enExample) |
| ES (1) | ES2515240T3 (enExample) |
| FR (1) | FR2944792B1 (enExample) |
| HR (1) | HRP20141058T1 (enExample) |
| IL (1) | IL215733A (enExample) |
| MX (1) | MX2011011246A (enExample) |
| MY (1) | MY156362A (enExample) |
| PL (1) | PL2421864T3 (enExample) |
| PT (1) | PT2421864E (enExample) |
| RU (1) | RU2530775C2 (enExample) |
| SG (1) | SG175338A1 (enExample) |
| SI (1) | SI2421864T1 (enExample) |
| TW (1) | TWI468405B (enExample) |
| UY (1) | UY32575A (enExample) |
| WO (1) | WO2010122272A1 (enExample) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109020972B (zh) * | 2018-10-08 | 2021-03-09 | 广东石油化工学院 | 一种三唑并[1，5-a]喹啉衍生物的制备方法 |
| WO2023039510A1 (en) * | 2021-09-10 | 2023-03-16 | The Trustees Of Columbia University In The City Of New York | Gpx4 inhibitors and uses thereof |
| CN116535356A (zh) * | 2023-03-06 | 2023-08-04 | 中国药科大学 | 3-氨基-5-苯基-吡唑类衍生物微管蛋白抑制剂及其制备和医药用途 |
| EP4506003A1 (en) | 2023-08-07 | 2025-02-12 | S.Yu Yunusov Institute of Chemistry of Plant Substances of the Academy of Sciences of the Republic of Uzbekistan | Halogen derivatives of (4´,5´- methylenedioxyphenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline for use in the treatment of leukemia |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8600752D0 (en) * | 1986-01-14 | 1986-02-19 | Roussel Lab Ltd | Chemical compounds |
| DE10229762A1 (de) * | 2002-07-03 | 2004-01-22 | Aventis Pharma Deutschland Gmbh | Pyrazoloisoquinolinenderivaten zur Inhibierung von NFkappaB-induzierende Kinase |
| US7132428B2 (en) * | 2003-07-03 | 2006-11-07 | Aventis Pharmaceuticals Inc. | Pyrazoloisoquinoline derivative as kinase inhibitors for the treatment of various disorders |
| CA2531291A1 (en) * | 2003-07-03 | 2005-02-10 | Aventis Pharmaceuticals Inc. | Pyrazoloisoquinoline derivatives as kinase inhibitors |
| AU2004259012C1 (en) * | 2003-07-23 | 2012-08-02 | Exelixis, Inc. | Anaplastic lymphoma kinase modulators and methods of use |
| AR058223A1 (es) * | 2005-11-25 | 2008-01-23 | Palau Pharma Sa | Un comuesto de derivados de pirazoloisoquinolina, un procedimiento para l a preparacion de dicho compuesto y una composicion farmaceutica que comprende dicho compuesto |
-
2009
- 2009-04-24 FR FR0901995A patent/FR2944792B1/fr not_active Expired - Fee Related
-
2010
- 2010-04-22 CA CA2791947A patent/CA2791947A1/fr not_active Abandoned
- 2010-04-22 SI SI201030757T patent/SI2421864T1/sl unknown
- 2010-04-22 MY MYPI2011005108A patent/MY156362A/en unknown
- 2010-04-22 ES ES10723723.2T patent/ES2515240T3/es active Active
- 2010-04-22 HR HRP20141058AT patent/HRP20141058T1/hr unknown
- 2010-04-22 US US13/265,981 patent/US8461175B2/en not_active Expired - Fee Related
- 2010-04-22 BR BRPI1013724A patent/BRPI1013724A2/pt not_active IP Right Cessation
- 2010-04-22 SG SG2011077963A patent/SG175338A1/en unknown
- 2010-04-22 EP EP10723723.2A patent/EP2421864B1/fr active Active
- 2010-04-22 CN CN201080028355.1A patent/CN102459260B/zh not_active Expired - Fee Related
- 2010-04-22 MX MX2011011246A patent/MX2011011246A/es active IP Right Grant
- 2010-04-22 PT PT107237232T patent/PT2421864E/pt unknown
- 2010-04-22 PL PL10723723T patent/PL2421864T3/pl unknown
- 2010-04-22 KR KR1020117027900A patent/KR101675609B1/ko not_active Expired - Fee Related
- 2010-04-22 AU AU2010240742A patent/AU2010240742B2/en not_active Ceased
- 2010-04-22 JP JP2012506551A patent/JP5722880B2/ja not_active Expired - Fee Related
- 2010-04-22 DK DK10723723.2T patent/DK2421864T3/da active
- 2010-04-22 RU RU2011147658/04A patent/RU2530775C2/ru not_active IP Right Cessation
- 2010-04-22 WO PCT/FR2010/050773 patent/WO2010122272A1/fr not_active Ceased
- 2010-04-23 UY UY0001032575A patent/UY32575A/es not_active Application Discontinuation
- 2010-04-23 TW TW99112914A patent/TWI468405B/zh not_active IP Right Cessation
- 2010-04-23 AR ARP100101357A patent/AR076393A1/es unknown
-
2011
- 2011-10-11 IL IL215733A patent/IL215733A/en not_active IP Right Cessation
-
2014
- 2014-10-30 CY CY20141100897T patent/CY1115678T1/el unknown
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request |
Effective date: 20150323 |
|
| FZDE | Discontinued |
Effective date: 20181120 |