PT2350080E - Dímeros de pirrolobenzodiazepina assimétricos para o tratamento de doenças proliferativas - Google Patents

Info

Publication number

PT2350080E

PT2350080E PT97401855T PT09740185T PT2350080E PT 2350080 E PT2350080 E PT 2350080E PT 97401855 T PT97401855 T PT 97401855T PT 09740185 T PT09740185 T PT 09740185T PT 2350080 E PT2350080 E PT 2350080E

Authority

PT

Portugal

Prior art keywords

group

compound according

mmol

compound

methoxy

Prior art date

2008-10-17

Links

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• 238000011282 treatment Methods 0.000 title claims description 12
• 230000002062 proliferating effect Effects 0.000 title claims description 8
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims description 7
• 201000010099 disease Diseases 0.000 title claims description 6
• 239000000539 dimer Substances 0.000 title description 7
• -1 2,2,2-trichloroethoxycarbonyl Chemical group 0.000 claims description 147
• 150000001875 compounds Chemical class 0.000 claims description 87
• 125000003118 aryl group Chemical group 0.000 claims description 67
• 125000000623 heterocyclic group Chemical group 0.000 claims description 53
• 238000000034 method Methods 0.000 claims description 36
• 125000001424 substituent group Chemical group 0.000 claims description 35
• 125000000217 alkyl group Chemical group 0.000 claims description 23
• 125000003277 amino group Chemical group 0.000 claims description 20
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 18
• 125000002947 alkylene group Chemical group 0.000 claims description 18
• 229910052739 hydrogen Inorganic materials 0.000 claims description 16
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 13
• 125000005843 halogen group Chemical group 0.000 claims description 12
• 229910052757 nitrogen Inorganic materials 0.000 claims description 12
• 125000003545 alkoxy group Chemical group 0.000 claims description 11
• 125000004432 carbon atom Chemical group C* 0.000 claims description 11
• 150000001768 cations Chemical class 0.000 claims description 11
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
• 229910052727 yttrium Inorganic materials 0.000 claims description 11
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 10
• LJCZNYWLQZZIOS-UHFFFAOYSA-N 2,2,2-trichlorethoxycarbonyl chloride Chemical compound ClC(=O)OCC(Cl)(Cl)Cl LJCZNYWLQZZIOS-UHFFFAOYSA-N 0.000 claims description 9
• 125000004043 oxo group Chemical group O=* 0.000 claims description 8
• 239000003814 drug Substances 0.000 claims description 7
• 125000005842 heteroatom Chemical group 0.000 claims description 7
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
• 125000001072 heteroaryl group Chemical group 0.000 claims description 6
• 229910052760 oxygen Inorganic materials 0.000 claims description 6
• 229910052717 sulfur Inorganic materials 0.000 claims description 6
• 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 6
• 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 5
• 125000003342 alkenyl group Chemical group 0.000 claims description 5
• 125000000304 alkynyl group Chemical group 0.000 claims description 5
• 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 5
• 230000000694 effects Effects 0.000 claims description 4
• ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims description 4
• 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
• 125000004104 aryloxy group Chemical group 0.000 claims description 3
• 125000005844 heterocyclyloxy group Chemical group 0.000 claims description 3
• 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 claims description 2
• 125000000172 C5-C10 aryl group Chemical group 0.000 claims description 2
• 238000004519 manufacturing process Methods 0.000 claims description 2
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 1
• QWYTUBPAXJYCTH-UHFFFAOYSA-N 2-trimethylsilylethyl carbamate Chemical compound C[Si](C)(C)CCOC(N)=O QWYTUBPAXJYCTH-UHFFFAOYSA-N 0.000 claims 1
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• 125000006701 (C1-C7) alkyl group Chemical group 0.000 description 58
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 56
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 54
• 239000000243 solution Substances 0.000 description 53
• 239000011541 reaction mixture Substances 0.000 description 51
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• 235000019439 ethyl acetate Nutrition 0.000 description 42
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• 238000004949 mass spectrometry Methods 0.000 description 37
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• 238000003756 stirring Methods 0.000 description 33
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• 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 25
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• 239000002904 solvent Substances 0.000 description 24
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• 239000007787 solid Substances 0.000 description 21
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• 229940088710 antibiotic agent Drugs 0.000 description 20
• 239000012043 crude product Substances 0.000 description 20
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 19
• 235000019341 magnesium sulphate Nutrition 0.000 description 19
• 239000000741 silica gel Substances 0.000 description 19
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• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
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• 238000006243 chemical reaction Methods 0.000 description 18
• 238000003818 flash chromatography Methods 0.000 description 18
• PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 18
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 17
• 239000000203 mixture Substances 0.000 description 17
• 125000006413 ring segment Chemical group 0.000 description 17
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 16
• 239000012044 organic layer Substances 0.000 description 16
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
• 125000006239 protecting group Chemical group 0.000 description 15
• 239000011734 sodium Substances 0.000 description 15
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 14
• 125000004435 hydrogen atom Chemical group [H]* 0.000 description 13
• 238000002390 rotary evaporation Methods 0.000 description 13
• DCZYHHJEQINFHD-UHFFFAOYSA-N 1,2-dihydro-1,4-benzodiazepin-5-one Chemical compound O=C1N=CCNC2=CC=CC=C12 DCZYHHJEQINFHD-UHFFFAOYSA-N 0.000 description 12
• 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 12
• 239000006260 foam Substances 0.000 description 12
• 239000012634 fragment Substances 0.000 description 12
• 239000001257 hydrogen Substances 0.000 description 12
• 239000012299 nitrogen atmosphere Substances 0.000 description 12
• 238000000746 purification Methods 0.000 description 12
• 238000004809 thin layer chromatography Methods 0.000 description 12
• 241000790917 Dioxys <bee> Species 0.000 description 11
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 11
• 239000003480 eluent Substances 0.000 description 11
• 238000001704 evaporation Methods 0.000 description 11
• 230000008020 evaporation Effects 0.000 description 11
• 238000001914 filtration Methods 0.000 description 11
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 11
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 11
• 229920006395 saturated elastomer Polymers 0.000 description 11
• 239000012071 phase Substances 0.000 description 10
• 238000002360 preparation method Methods 0.000 description 10
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• 150000003839 salts Chemical class 0.000 description 10
• 239000003643 water by type Substances 0.000 description 10
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• 238000010828 elution Methods 0.000 description 8
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