DK3057959T3 - INHIBITORS FOR DNA PK - Google Patents

Info

Publication number

DK3057959T3

DK3057959T3 DK14800181.1T DK14800181T DK3057959T3 DK 3057959 T3 DK3057959 T3 DK 3057959T3 DK 14800181 T DK14800181 T DK 14800181T DK 3057959 T3 DK3057959 T3 DK 3057959T3

Authority

DK

Denmark

Prior art keywords

pharmaceutisk

sammensætning

eller

compound

accepterbart

Prior art date

2013-10-17

Links

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• 239000003112 inhibitor Substances 0.000 title abstract description 14
• 206010028980 Neoplasm Diseases 0.000 claims description 66
• 201000011510 cancer Diseases 0.000 claims description 34
• 150000003839 salts Chemical class 0.000 claims description 33
• 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 3
• 208000005017 glioblastoma Diseases 0.000 claims description 3
• 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 3
• 201000001441 melanoma Diseases 0.000 claims description 3
• 208000008443 pancreatic carcinoma Diseases 0.000 claims description 3
• 201000008808 Fibrosarcoma Diseases 0.000 claims description 2
• 150000001875 compounds Chemical class 0.000 abstract description 253
• 239000000203 mixture Substances 0.000 abstract description 96
• 238000000034 method Methods 0.000 abstract description 30
• 238000011282 treatment Methods 0.000 abstract description 16
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 11
• 201000010099 disease Diseases 0.000 abstract description 7
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 129
• -1 4,6-disubstituted aminopyrimidine compounds Chemical class 0.000 description 127
• YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 105
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 81
• 230000002829 reductive effect Effects 0.000 description 80
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 70
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 70
• 239000000243 solution Substances 0.000 description 69
• 239000011541 reaction mixture Substances 0.000 description 68
• 229910001868 water Inorganic materials 0.000 description 66
• 238000005160 1H NMR spectroscopy Methods 0.000 description 65
• 235000019439 ethyl acetate Nutrition 0.000 description 63
• 239000007787 solid Substances 0.000 description 55
• 238000006243 chemical reaction Methods 0.000 description 43
• 229910052739 hydrogen Inorganic materials 0.000 description 41
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 37
• 239000001257 hydrogen Substances 0.000 description 37
• 125000000217 alkyl group Chemical group 0.000 description 36
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 35
• 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 33
• 108010006124 DNA-Activated Protein Kinase Proteins 0.000 description 32
• 125000000623 heterocyclic group Chemical group 0.000 description 32
• 102000005768 DNA-Activated Protein Kinase Human genes 0.000 description 31
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 29
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 28
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 28
• WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 27
• 125000001153 fluoro group Chemical group F* 0.000 description 26
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
• 239000000706 filtrate Substances 0.000 description 23
• OYRRZWATULMEPF-UHFFFAOYSA-N pyrimidin-4-amine Chemical compound NC1=CC=NC=N1 OYRRZWATULMEPF-UHFFFAOYSA-N 0.000 description 23
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 22
• 238000001914 filtration Methods 0.000 description 22
• KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 22
• 238000010898 silica gel chromatography Methods 0.000 description 22
• 239000000725 suspension Substances 0.000 description 22
• 235000002639 sodium chloride Nutrition 0.000 description 21
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 20
• 210000004027 cell Anatomy 0.000 description 20
• 238000002360 preparation method Methods 0.000 description 20
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 18
• 150000002431 hydrogen Chemical group 0.000 description 18
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 17
• 239000012298 atmosphere Substances 0.000 description 17
• 125000001072 heteroaryl group Chemical group 0.000 description 17
• 239000003039 volatile agent Substances 0.000 description 17
• 125000002887 hydroxy group Chemical group [H]O* 0.000 description 16
• 239000012267 brine Substances 0.000 description 15
• 229910000029 sodium carbonate Inorganic materials 0.000 description 15
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 15
• 239000005909 Kieselgur Substances 0.000 description 14
• BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 14
• XMIIGOLPHOKFCH-UHFFFAOYSA-N beta-phenylpropanoic acid Natural products OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 14
• 230000005865 ionizing radiation Effects 0.000 description 14
• 239000002244 precipitate Substances 0.000 description 14
• 125000001424 substituent group Chemical group 0.000 description 14
• KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 13
• 125000003118 aryl group Chemical group 0.000 description 13
• 239000003795 chemical substances by application Substances 0.000 description 13
• 238000001816 cooling Methods 0.000 description 13
• 230000000694 effects Effects 0.000 description 13
• 229910052736 halogen Inorganic materials 0.000 description 13
• 150000002367 halogens Chemical group 0.000 description 13
• 125000002757 morpholinyl group Chemical group 0.000 description 13
• 229910052757 nitrogen Inorganic materials 0.000 description 13
• 238000003756 stirring Methods 0.000 description 13
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
• 108020004414 DNA Proteins 0.000 description 12
• 125000004122 cyclic group Chemical group 0.000 description 12
• 239000003921 oil Substances 0.000 description 12
• 235000019198 oils Nutrition 0.000 description 12
• 239000000047 product Substances 0.000 description 12
• 239000000741 silica gel Substances 0.000 description 12
• 229910002027 silica gel Inorganic materials 0.000 description 12
• KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 11
• GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 11
• 125000004429 atom Chemical group 0.000 description 11
• 229910052799 carbon Inorganic materials 0.000 description 11
• 239000000284 extract Substances 0.000 description 11
• 230000005764 inhibitory process Effects 0.000 description 11
• 239000010410 layer Substances 0.000 description 11
• 239000002904 solvent Substances 0.000 description 11
• 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 10
• ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 10
• 229910001873 dinitrogen Inorganic materials 0.000 description 10
• 239000002552 dosage form Substances 0.000 description 10
• 239000003814 drug Substances 0.000 description 10
• 235000019441 ethanol Nutrition 0.000 description 10
• 239000000463 material Substances 0.000 description 10
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 10
• 125000003386 piperidinyl group Chemical group 0.000 description 10
• 125000000719 pyrrolidinyl group Chemical group 0.000 description 10
• CBFHHXZSENSSMA-UHFFFAOYSA-N quinazoline-4-carboxamide Chemical compound C1=CC=C2C(C(=O)N)=NC=NC2=C1 CBFHHXZSENSSMA-UHFFFAOYSA-N 0.000 description 10
• XJPZKYIHCLDXST-UHFFFAOYSA-N 4,6-dichloropyrimidine Chemical compound ClC1=CC(Cl)=NC=N1 XJPZKYIHCLDXST-UHFFFAOYSA-N 0.000 description 9
• DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
• 125000000753 cycloalkyl group Chemical group 0.000 description 9
• 229910052731 fluorine Inorganic materials 0.000 description 9
• 239000000543 intermediate Substances 0.000 description 9
• 229920006395 saturated elastomer Polymers 0.000 description 9
• 210000001519 tissue Anatomy 0.000 description 9
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
• 102100022204 DNA-dependent protein kinase catalytic subunit Human genes 0.000 description 8
• 101710157074 DNA-dependent protein kinase catalytic subunit Proteins 0.000 description 8
• OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 8
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
• BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 8
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• 238000004587 chromatography analysis Methods 0.000 description 8
• 230000005782 double-strand break Effects 0.000 description 8
• 239000007788 liquid Substances 0.000 description 8
• HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
• 125000003566 oxetanyl group Chemical group 0.000 description 8
• 239000000546 pharmaceutical excipient Substances 0.000 description 8
• 125000004193 piperazinyl group Chemical group 0.000 description 8
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 8
• 238000004808 supercritical fluid chromatography Methods 0.000 description 8
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 8
• 210000004881 tumor cell Anatomy 0.000 description 8
• 239000003981 vehicle Substances 0.000 description 8
• 229940126289 DNA-PK inhibitor Drugs 0.000 description 7
• DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 7
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• 239000002775 capsule Substances 0.000 description 7
• 239000003937 drug carrier Substances 0.000 description 7
• 239000008101 lactose Substances 0.000 description 7
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• PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 6
• WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
• PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
• 241001465754 Metazoa Species 0.000 description 6
• NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
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• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
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• FKHIFSZMMVMEQY-UHFFFAOYSA-N talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 description 6
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• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
• GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 5
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