PT2668184T - Derivados do tipo azaindazole ou diazaindazole utilizados como medicamentos - Google Patents

Info

Publication number

PT2668184T

PT2668184T PT127018844T PT12701884T PT2668184T PT 2668184 T PT2668184 T PT 2668184T PT 127018844 T PT127018844 T PT 127018844T PT 12701884 T PT12701884 T PT 12701884T PT 2668184 T PT2668184 T PT 2668184T

Authority

PT

Portugal

Prior art keywords

mmol

group

charom

compound

reaction

Prior art date

2011-01-27

Links

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• 239000003814 drug Substances 0.000 title claims description 9
• VQNDBXJTIJKJPV-UHFFFAOYSA-N 2h-triazolo[4,5-b]pyridine Chemical compound C1=CC=NC2=NNN=C21 VQNDBXJTIJKJPV-UHFFFAOYSA-N 0.000 title 1
• QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical class C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 title 1
• 238000000034 method Methods 0.000 claims description 161
• 150000001875 compounds Chemical class 0.000 claims description 154
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 49
• 206010028980 Neoplasm Diseases 0.000 claims description 33
• 229910052757 nitrogen Inorganic materials 0.000 claims description 30
• 229910052717 sulfur Inorganic materials 0.000 claims description 29
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 28
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 21
• 150000003839 salts Chemical class 0.000 claims description 21
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 20
• 125000003118 aryl group Chemical group 0.000 claims description 19
• 201000011510 cancer Diseases 0.000 claims description 16
• 238000011282 treatment Methods 0.000 claims description 16
• 238000005859 coupling reaction Methods 0.000 claims description 15
• 125000005843 halogen group Chemical group 0.000 claims description 14
• 102000001332 SRC Human genes 0.000 claims description 13
• 108060006706 SRC Proteins 0.000 claims description 13
• 108091000080 Phosphotransferase Proteins 0.000 claims description 12
• 238000010511 deprotection reaction Methods 0.000 claims description 12
• 125000000623 heterocyclic group Chemical group 0.000 claims description 12
• 102000020233 phosphotransferase Human genes 0.000 claims description 12
• 238000002360 preparation method Methods 0.000 claims description 12
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 11
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 10
• 125000004432 carbon atom Chemical group C* 0.000 claims description 9
• 201000010099 disease Diseases 0.000 claims description 9
• 239000008194 pharmaceutical composition Substances 0.000 claims description 9
• 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 7
• 230000008878 coupling Effects 0.000 claims description 7
• 238000010168 coupling process Methods 0.000 claims description 7
• 229940079593 drug Drugs 0.000 claims description 7
• 229910052760 oxygen Inorganic materials 0.000 claims description 7
• 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 6
• 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 claims description 6
• 239000003112 inhibitor Substances 0.000 claims description 6
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
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• 239000004480 active ingredient Substances 0.000 claims description 4
• 125000000217 alkyl group Chemical group 0.000 claims description 3
• 229910052721 tungsten Inorganic materials 0.000 claims description 3
• 101150020251 NR13 gene Proteins 0.000 claims description 2
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
• 125000003107 substituted aryl group Chemical group 0.000 claims description 2
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• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 168
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 154
• 239000000243 solution Substances 0.000 description 142
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 123
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 102
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• 239000007787 solid Substances 0.000 description 90
• -1 Kit Proteins 0.000 description 89
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 76
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• 238000006243 chemical reaction Methods 0.000 description 71
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• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 66
• 239000002904 solvent Substances 0.000 description 66
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• 235000019439 ethyl acetate Nutrition 0.000 description 60
• 239000012074 organic phase Substances 0.000 description 58
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 54
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• 238000005481 NMR spectroscopy Methods 0.000 description 46
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 40
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• 238000005160 1H NMR spectroscopy Methods 0.000 description 37
• 238000010586 diagram Methods 0.000 description 36
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 36
• 235000019341 magnesium sulphate Nutrition 0.000 description 36
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 33
• OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 32
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 27
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 25
• 230000000875 corresponding effect Effects 0.000 description 25
• 239000000047 product Substances 0.000 description 25
• 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 24
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 23
• 238000010898 silica gel chromatography Methods 0.000 description 23
• 230000015572 biosynthetic process Effects 0.000 description 22
• 238000003756 stirring Methods 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 21
• KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 21
• 239000002798 polar solvent Substances 0.000 description 21
• 102100033793 ALK tyrosine kinase receptor Human genes 0.000 description 20
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 20
• 101000779641 Homo sapiens ALK tyrosine kinase receptor Proteins 0.000 description 20
• XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 20
• 239000000843 powder Substances 0.000 description 19
• 239000002244 precipitate Substances 0.000 description 19
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 18
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
• 239000007795 chemical reaction product Substances 0.000 description 18
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 17
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 17
• 239000000543 intermediate Substances 0.000 description 17
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 17
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
• 150000007529 inorganic bases Chemical class 0.000 description 16
• 150000007530 organic bases Chemical class 0.000 description 16
• 125000006239 protecting group Chemical group 0.000 description 16
• JVVRJMXHNUAPHW-UHFFFAOYSA-N 1h-pyrazol-5-amine Chemical class NC=1C=CNN=1 JVVRJMXHNUAPHW-UHFFFAOYSA-N 0.000 description 14
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
• 239000002585 base Substances 0.000 description 14
• LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 13
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 13
• 238000005755 formation reaction Methods 0.000 description 13
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 13
• NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 12
• 239000003795 chemical substances by application Substances 0.000 description 12
• 239000000460 chlorine Substances 0.000 description 12
• 229910000027 potassium carbonate Inorganic materials 0.000 description 12
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 12
• 208000032004 Large-Cell Anaplastic Lymphoma Diseases 0.000 description 11
• 229910052786 argon Inorganic materials 0.000 description 11
• 239000013078 crystal Substances 0.000 description 11
• 239000003480 eluent Substances 0.000 description 11
• 238000003786 synthesis reaction Methods 0.000 description 11
• 206010073478 Anaplastic large-cell lymphoma Diseases 0.000 description 10
• DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 10
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 10
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 10
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• 238000000746 purification Methods 0.000 description 10
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• 229910000029 sodium carbonate Inorganic materials 0.000 description 10
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• NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 7
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• INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 6
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• 238000001727 in vivo Methods 0.000 description 5
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