DK2197874T3 - Pyrazin-2-YL-PYRIDIN-2-YL-AMINE AND pyrazin-2-yl-pyrimidine-4-YL-AMINE COMPOUNDS AND THEIR USE - Google Patents

Info

Publication number

DK2197874T3

DK2197874T3 DK08806506.5T DK08806506T DK2197874T3 DK 2197874 T3 DK2197874 T3 DK 2197874T3 DK 08806506 T DK08806506 T DK 08806506T DK 2197874 T3 DK2197874 T3 DK 2197874T3

Authority

DK

Denmark

Prior art keywords

independently

ylamino

synthesis

alkyl

optionally substituted

Prior art date

2007-10-05

Links

• Espacenet
• Global Dossier
• Discuss

• IXZMTZOSMOHJMU-UHFFFAOYSA-N n-pyrazin-2-ylpyrimidin-4-amine Chemical class C=1N=CC=NC=1NC1=CC=NC=N1 IXZMTZOSMOHJMU-UHFFFAOYSA-N 0.000 title description 4
• GOYIJZBEFGZUSR-UHFFFAOYSA-N n-pyridin-2-ylpyrazin-2-amine Chemical compound C=1N=CC=NC=1NC1=CC=CC=N1 GOYIJZBEFGZUSR-UHFFFAOYSA-N 0.000 title description 3
• 150000001875 compounds Chemical class 0.000 claims description 323
• 238000000034 method Methods 0.000 claims description 191
• -1 pyrrolidino, piperidino, piperazino Chemical group 0.000 claims description 169
• 238000011282 treatment Methods 0.000 claims description 119
• 125000001931 aliphatic group Chemical group 0.000 claims description 111
• 206010028980 Neoplasm Diseases 0.000 claims description 69
• 239000003795 chemical substances by application Substances 0.000 claims description 69
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 55
• 239000003112 inhibitor Substances 0.000 claims description 52
• 201000011510 cancer Diseases 0.000 claims description 51
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 49
• 125000003118 aryl group Chemical group 0.000 claims description 32
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 31
• 230000005764 inhibitory process Effects 0.000 claims description 30
• 239000012623 DNA damaging agent Substances 0.000 claims description 24
• 230000000340 anti-metabolite Effects 0.000 claims description 24
• 229940100197 antimetabolite Drugs 0.000 claims description 24
• 239000002256 antimetabolite Substances 0.000 claims description 24
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 24
• 125000001424 substituent group Chemical group 0.000 claims description 24
• 102000003915 DNA Topoisomerases Human genes 0.000 claims description 23
• 108090000323 DNA Topoisomerases Proteins 0.000 claims description 23
• 102000007537 Type II DNA Topoisomerases Human genes 0.000 claims description 23
• 108010046308 Type II DNA Topoisomerases Proteins 0.000 claims description 23
• 239000003814 drug Substances 0.000 claims description 21
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 19
• 230000001404 mediated effect Effects 0.000 claims description 19
• 150000003839 salts Chemical class 0.000 claims description 18
• 238000002560 therapeutic procedure Methods 0.000 claims description 17
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 15
• 125000000217 alkyl group Chemical group 0.000 claims description 14
• 201000010099 disease Diseases 0.000 claims description 14
• 239000008194 pharmaceutical composition Substances 0.000 claims description 14
• 239000003085 diluting agent Substances 0.000 claims description 12
• 229920006395 saturated elastomer Polymers 0.000 claims description 12
• 239000012453 solvate Substances 0.000 claims description 12
• 230000002062 proliferating effect Effects 0.000 claims description 11
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 10
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 10
• 206010009944 Colon cancer Diseases 0.000 claims description 9
• 238000004519 manufacturing process Methods 0.000 claims description 9
• 201000001441 melanoma Diseases 0.000 claims description 9
• 125000001544 thienyl group Chemical group 0.000 claims description 9
• 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 8
• 239000003937 drug carrier Substances 0.000 claims description 8
• 206010006187 Breast cancer Diseases 0.000 claims description 7
• 208000026310 Breast neoplasm Diseases 0.000 claims description 7
• 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 7
• 206010033128 Ovarian cancer Diseases 0.000 claims description 7
• 206010061535 Ovarian neoplasm Diseases 0.000 claims description 7
• 201000005202 lung cancer Diseases 0.000 claims description 7
• 208000020816 lung neoplasm Diseases 0.000 claims description 7
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 6
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 6
• 101000777293 Homo sapiens Serine/threonine-protein kinase Chk1 Proteins 0.000 claims description 6
• 241001465754 Metazoa Species 0.000 claims description 6
• 102100031081 Serine/threonine-protein kinase Chk1 Human genes 0.000 claims description 6
• 230000005865 ionizing radiation Effects 0.000 claims description 4
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
• 101100079135 Arabidopsis thaliana NAC92 gene Proteins 0.000 claims description 2
• 101100231811 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) HSP150 gene Proteins 0.000 claims description 2
• 125000002947 alkylene group Chemical group 0.000 claims 15
• 210000004498 neuroglial cell Anatomy 0.000 claims 2
• 101150110809 ORM1 gene Proteins 0.000 claims 1
• 125000000392 cycloalkenyl group Chemical group 0.000 claims 1
• 125000000753 cycloalkyl group Chemical group 0.000 claims 1
• 125000001072 heteroaryl group Chemical group 0.000 claims 1
• 238000003786 synthesis reaction Methods 0.000 description 377
• 230000015572 biosynthetic process Effects 0.000 description 373
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 356
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 266
• 238000005160 1H NMR spectroscopy Methods 0.000 description 182
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 164
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 163
• 239000000203 mixture Substances 0.000 description 142
• 239000000243 solution Substances 0.000 description 109
• 229910052739 hydrogen Inorganic materials 0.000 description 86
• 239000002904 solvent Substances 0.000 description 78
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 74
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 72
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 70
• 125000005842 heteroatom Chemical group 0.000 description 70
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 69
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 63
• 239000011541 reaction mixture Substances 0.000 description 61
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• 239000011347 resin Substances 0.000 description 45
• 229920005989 resin Polymers 0.000 description 45
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 43
• 230000002378 acidificating effect Effects 0.000 description 39
• 229910052757 nitrogen Inorganic materials 0.000 description 39
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 35
• 239000012043 crude product Substances 0.000 description 32
• 238000009472 formulation Methods 0.000 description 32
• 239000003921 oil Substances 0.000 description 32
• 235000019198 oils Nutrition 0.000 description 28
• 150000001412 amines Chemical class 0.000 description 27
• CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 27
• 238000003818 flash chromatography Methods 0.000 description 27
• 238000005342 ion exchange Methods 0.000 description 27
• OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 27
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 26
• 239000000377 silicon dioxide Substances 0.000 description 26
• 239000002585 base Substances 0.000 description 25
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 24
• 238000012746 preparative thin layer chromatography Methods 0.000 description 24
• QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 23
• 229910021529 ammonia Inorganic materials 0.000 description 23
• 102000029749 Microtubule Human genes 0.000 description 22
• 108091022875 Microtubule Proteins 0.000 description 22
• 238000010438 heat treatment Methods 0.000 description 22
• 210000004688 microtubule Anatomy 0.000 description 22
• 239000012074 organic phase Substances 0.000 description 22
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 20
• 239000008346 aqueous phase Substances 0.000 description 20
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 18
• 239000000543 intermediate Substances 0.000 description 17
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 17
• 230000005855 radiation Effects 0.000 description 17
• 239000000843 powder Substances 0.000 description 16
• 239000000047 product Substances 0.000 description 16
• 239000000725 suspension Substances 0.000 description 16
• 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 16
• 238000013459 approach Methods 0.000 description 15
• 238000006243 chemical reaction Methods 0.000 description 15
• 150000002148 esters Chemical class 0.000 description 15
• 239000007788 liquid Substances 0.000 description 15
• 229910000069 nitrogen hydride Inorganic materials 0.000 description 15
• 125000003386 piperidinyl group Chemical group 0.000 description 15
• 125000006239 protecting group Chemical group 0.000 description 15
• 238000007429 general method Methods 0.000 description 14
• 239000000741 silica gel Substances 0.000 description 14
• 229910002027 silica gel Inorganic materials 0.000 description 14
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 14
• 230000005778 DNA damage Effects 0.000 description 13
• 231100000277 DNA damage Toxicity 0.000 description 13
• 239000002253 acid Substances 0.000 description 13
• 238000003556 assay Methods 0.000 description 13
• 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 13
• 125000004433 nitrogen atom Chemical group N* 0.000 description 13
• 125000006574 non-aromatic ring group Chemical group 0.000 description 13
• 238000000746 purification Methods 0.000 description 13
• 125000000719 pyrrolidinyl group Chemical group 0.000 description 13
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 13
• 125000001412 tetrahydropyranyl group Chemical group 0.000 description 13
• 125000002757 morpholinyl group Chemical group 0.000 description 12
• 229910052763 palladium Inorganic materials 0.000 description 12
• 125000004193 piperazinyl group Chemical group 0.000 description 12
• 125000000524 functional group Chemical group 0.000 description 11
• 230000002401 inhibitory effect Effects 0.000 description 11
• 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 11
• PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 10
• CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 10
• 238000005576 amination reaction Methods 0.000 description 10
• 230000004663 cell proliferation Effects 0.000 description 10
• LNAMMBFJMYMQTO-FNEBRGMMSA-N chloroform;(1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].ClC(Cl)Cl.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 LNAMMBFJMYMQTO-FNEBRGMMSA-N 0.000 description 10
• 230000000694 effects Effects 0.000 description 10
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• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 10
• 229910000029 sodium carbonate Inorganic materials 0.000 description 10
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• DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 10
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
• VYANAPRTDDQFJY-UHFFFAOYSA-N 5-aminopyrazine-2-carbonitrile Chemical compound NC1=CN=C(C#N)C=N1 VYANAPRTDDQFJY-UHFFFAOYSA-N 0.000 description 9
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
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• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
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• 101150113535 chek1 gene Proteins 0.000 description 8
• OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 8
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• MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 8
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• YGDHJAMSJWLAFR-UHFFFAOYSA-N tert-butyl 3-[[[5-amino-2-[(5-cyanopyrazin-2-yl)amino]pyridin-4-yl]amino]methyl]piperidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC1CNC1=CC(NC=2N=CC(=NC=2)C#N)=NC=C1N YGDHJAMSJWLAFR-UHFFFAOYSA-N 0.000 description 8
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• 125000002883 imidazolyl group Chemical group 0.000 description 7
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• 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 7
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• 125000001425 triazolyl group Chemical group 0.000 description 7
• DEJUUKULVAIMNF-UHFFFAOYSA-N 2-chloro-5-iodopyridin-4-amine Chemical compound NC1=CC(Cl)=NC=C1I DEJUUKULVAIMNF-UHFFFAOYSA-N 0.000 description 6
• MCFUHWBBTIHPCP-UHFFFAOYSA-N 3-amino-2h-pyrazine-1-carbonitrile Chemical compound NC1=NC=CN(C#N)C1 MCFUHWBBTIHPCP-UHFFFAOYSA-N 0.000 description 6
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